After a fatal accident, the cheeky mouse Whizzy and the stuttering fox Whitebelly meet again in animal heaven. Once there, Whizzy and Whitebelly find swings, carousels and many other attractions.

The film centres on a group of office colleagues in downtown Calgary, Alberta, who bet a month's salary on who can last the longest without going outside by using the system of covered walkways that connect the buildings. The film takes place over one lunch hour on day 24 of the month-long competition. Things start to become complicated as the office prepares for the company founder's retirement party. The film's title is derived from a particular form of suicide where one smashes the (non-openable) window of one's high-rise office and then jumps through. In the movie, one of the characters has accumulated a 2-litre pop bottle full of marbles in the hopes of breaking his window. The dark joke for this is referenced in the film : "a 15 bus takes you downtown, a bottle of marbles takes you way downtown."

In 1959, on board a spacecraft, two aliens race to keep an experiment from being released by a third member of the crew. The seemingly possessed third alien shoots the canister into space where it crashes to Earth. Nearby, a college man takes his date to a parking spot when they see a falling star and investigate. It lands in the path of an escaped criminally insane patient. As his date is attacked by the axe-wielding maniac, the boy finds the canister, from which a small slug-like thing jumps out and into his mouth. Twenty-seven years later in 1986, Chris Romero pines over a love lost, supported by his disabled friend J.C. Hooper. During pledge week at Corman University, Chris spots a girl, Cynthia Cronenberg, and falls instantly in love. To get her attention, he decides to join a fraternity. Cynthia's boyfriend, who heads the Beta Epsilon fraternity, tasks them with stealing a cadaver from the university medical center and depositing it on the steps of a rival fraternity house. Chris and J.C. find a frozen corpse in a secret room, but when it grabs them, they flee. The thawed corpse then kills a medical student working at the lab. Detective Ray Cameron, a haunted cop, is called in to the cryogenics lab break-in, where he discovers one of the bodies – the boy who discovered the alien experiment in 1959 – is now missing, set free by Chris and J.C. The corpse makes its way back to the sorority house where he picked up his date twenty-seven years ago. There, his head splits open and releases more of the slugs. Called to the scene, Cameron finds the body, interpreting the condition of the head as the result of an axe wound in the face. The next day, the fraternity brothers confront Chris and J.C., who they believe to be responsible for the previous night's incident. They are then taken in for questioning by the police. Based on the testimony of a janitor who witnessed them running out of the university medical center, "screaming like banshees," they confess to breaking in but deny moving the corpse. That night, the dead medical student rises from his slab and runs into the janitor. Cynthia attempts to convince Chris and J.C. that the attacks are zombie-related, but they are skeptical. When J.C. sees Cynthia leaning on Chris' shoulder, J.C. leaves the two alone and is attacked by the slugs that emerge from the possessed janitor. After Chris walks Cynthia back to the sorority house, he runs into Cameron, who has overheard their conversation. At his house, Cameron explains to Chris that the escaped lunatic's 1959 victim was his ex-girlfriend, and that he secretly hunted down and killed the axe-murderer in revenge. After Cameron reveals that he buried the body under what is now the house mother’s house, he gets a call that the same axe-wielding lunatic has killed the house mother. Cameron blows off the corpse's head with his shotgun, which releases more slugs. The next night, while everyone prepares for a formal dance, Chris finds a recorded message that J.C. posthumously left for him. J.C. says that the slugs have incubated in his brain, but he has discovered that they are susceptible to heat. He confesses his love to Chris, and wishes him luck with Cynthia. Chris recruits Cameron, who was in the midst of a suicide attempt, and they retrieve a flamethrower from the police armory. They arrive at the sorority house just as Cynthia breaks up with Brad, who has become possessed. After killing him, the Beta fraternity brothers show up, despite having been killed in a bus crash. Cynthia and Chris team up to destroy the outside zombies while Cameron clears the house. After they stop the horde, Chris spots more slugs racing toward the basement; Cynthia explains that a member of the sorority had received specimen brains for biology class. In the basement, they find an enormous pile of slugs and Cameron, tape across his mouth, prepping a can of gasoline. The detective begins counting down as he splashes gasoline and Chris counts down in sync with him as he and Cynthia race out of the house. As Cameron opens up the house's gas valve, several slugs leap to attack him. He flicks his lighter and the house goes up in a fiery explosion. Chris and Cynthia share a kiss as they watch the house burn.

Mel Funn, a once-great Hollywood film director, is now recovering from a drinking problem and down on his luck. He and his sidekicks, Marty Eggs and Dom Bell, want to make the first silent movie in 40 years and Funn pitches the idea to the chief of Big Picture Studios. The chief rejects the idea at first but Funn convinces him that if he can get Hollywood's biggest stars to be in the film, it could save the studio from a takeover by New York conglomerate Engulf & Devour. Funn, Eggs and Bell proceed to recruit various stars for the film. They surprise Burt Reynolds in his shower and revisit his mansion in disguise. They recruit James Caan filming on location, following slapstick fumbling in an unstable dressing room trailer. They find Liza Minnelli at the studio commissary, where she eagerly agrees to be in the film. They recruit Anne Bancroft by disguising themselves as nightclub Flamenco dancers. While visiting the ailing studio chief in the hospital, Funn phones mime artist Marcel Marceau, who responds in French with the only spoken word in the film: a resounding Non! Bell asks, "What did he say?" Funn responds, "I don't know. I don't speak French!" They see Paul Newman on the hospital grounds and sign him to the film after a wild electric-wheelchair chase. In the course of their search for stars, the trio have a number of brief misadventures, including a mix-up between a seeing-eye dog and an untrained look-alike, several (mostly unsuccessful) efforts by Eggs to approach various women and a Coca-Cola vending machine that launches cans like grenades. Engulf & Devour learn of the project and try to sabotage it by sending voluptuous nightclub sensation Vilma Kaplan to seduce Funn. He falls for her but returns to drinking when he learns that she was part of a scheme. He buys a huge bottle of liquor and drinks himself into a stupor, surrounded by fellow "winos". Kaplan has genuinely fallen for Funn and refused Engulf & Devour's money; she helps Eggs and Bell find him and restore him to sobriety. The film is completed but the only copy is stolen by Engulf & Devour just before its theatrical premiere. Kaplan stalls the audience with her nightclub act, while Funn, Eggs and Bell successfully steal the film back. They are cornered by Engulf & Devour's thuggish executives but use the Coke machine they encountered earlier to attack and subdue them with exploding cans. Lacking a separate spool to rewind the film, Eggs winds the film around his own body and upon returning to the theater he has to be rushed to the projection booth to show it. The film is a huge success with the audience, which erupts with over-the-top applause. The studio is saved and Funn, Eggs, Bell, Kaplan and Chief celebrate, as an onscreen caption identifies the film as a "true story".

Although the film does not have a linear plot, a structure exists, telling the same story from three different perspectives. At the beginning, Soderbergh speaks to the audience in a style meant to evoke Cecil B. DeMille's introduction to The Ten Commandments. Fletcher Munson is an office employee working under Theodore Azimuth Schwitters, the leader of a self-help company known as Eventualism. The first part of the film is seen from Fletcher's perspective, seeing the underlying meaning in everything. He pays more attention to meaning, rather than what is said. He shows less and less attention to other people, to the point where he comes home and communicates with his wife by describing what they are saying. When Fletcher's co-worker Lester Richards dies, Fletcher takes his job as speechwriter. His personal life suffers because of this. He becomes more detached from his wife, who copes by having an affair. Meanwhile, Elmo Oxygen, an exterminator, goes from house to house, bedding the housewives who work for Schwitters. In each house he takes pictures of his genitals using cameras he finds. Elmo and the women speak in a nonsensical code. Fletcher's key will not work in his car door. He looks around to find that his actual car (parked two spots away) is an exact match for the one he is trying to get into. He goes to enter his car when he sees a man who is his exact double get into the car he just tried to enter. Fletcher follows his doppelgänger home, closes his eyes, and becomes him. Next we follow Fletcher's doppelgänger, Dr. Jeffrey Korchek, a dentist. He always wears a jogging suit. He is also a fan of Muzak, and is the mystery man that Fletcher's wife has been sleeping with. Korchek suggests she leave Fletcher for him. The next day, Korchek has breakfast with his heroin -addicted brother, who asks to stay with Korchek and for money. Korchek says that his brother should not be dealing with drug dealers and that he can get him drugs. Korchek goes to work, where he meets Attractive Woman Number 2, Mrs. Munson's doppelgänger. Korchek falls instantly in love and writes her a letter professing such. He leaves the note and goes home, where he sees a car in the driveway. It is Mrs. Munson, who has left Fletcher. Korchek admits that he has fallen in love with someone else. Mrs. Munson is upset and leaves. The next day Korchek gets to work and is confronted by a man who says "Your brother, eight hours, fifteen thousand dollars." Almost all of his dialog consists of these three commands. Korchek goes into the office and finds a letter from a law firm representing Attractive Woman Number 2, who is filing a sexual harassment suit against him. He discovers that his brother has stolen all of his money. Korchek leaves work. Korchek is shot dead. A couple following Elmo approach him, to convince him to stop playing his role in the film, in order to become a star in an action show. Unlike the rest of the film, Elmo's storyline moves forward in time. Finally we see the perspective of Mrs. Munson. We move through the storyline, seeing her experiences with Fletcher and Dr. Korchek and being a mom. The events are the same but Fletcher and Korchek speak foreign languages, similar to the "generic greetings" from earlier. Once Mrs. Munson leaves Korchek, she reconciles with Fletcher and they go home. Fletcher finishes Schwitters' speech. Schwitters mounts the podium and gives the oration. After Schwitters acknowledges the applause with a "Thank you," Elmo bursts in and shoots him in the shoulder. Schwitters survives and Elmo is arrested and interrogated. In a shopping mall Fletcher narrates events from the rest of his life. Then, Soderbergh returns in front of a blank movie screen and asks if there are any questions. After offering several responses he walks offstage as the camera pulls back to reveal he's been talking to an empty auditorium. A man clad only in a black T-shirt appears at the beginning and conclusion of the film, being chased by men in white coats through a field. In the beginning, the T-shirt sports the title of the film; later, it says "The End." The film has no beginning or end credits, although the fictitious persons and copyright disclaimers flash for a millisecond to conclude the film.

Living in her rundown van while travelling around America, homeless teenager Tallulah and her boyfriend Nico survive the streets by stealing credit cards. When Nico decides it is time to go home to his mother, Tallulah expresses her dismay and argues with Nico about how she will not change her lifestyle. Tallulah is devastated to discover the next morning that Nico has left without saying goodbye. Desperate to be with him again, Tallulah drives to New York City, where Nico's mother, Margo, lives and finds her at her apartment. After informing Tallulah that she has not seen Nico in two years, Margo tells Tallulah to leave. With nowhere else to go, Tallulah steals from guests at a nearby hotel, only for the strange natured and intoxicated mother, Carolyn, to mistake Tallulah as housekeeping staff. To Tallulah's confusion, Carolyn lets her child wander around naked and play with dangerous objects and admits that she is not invested in being a mother. Carolyn leaves her toddler, Maddison (Maddy), in Tallulah's care, while she goes on a date with a man who is not her husband. Tallulah bonds with the young Maddy, bathing her and playing games, before a devastated Carolyn arrives back at the hotel, distraught that the man did not want her. After Carolyn drunkenly passes out, Tallulah prepares to leave, but impulsively decides to take a crying Maddy back to her van to spend the night until further notice. When Tallulah returns to the hotel with Maddy, she flees upon seeing the police, summoned by a panicked Carolyn, and goes to Margo's apartment. After Tallulah claims that the child is Nico's and that she is Margo's granddaughter, "Maggie," Margo reluctantly agrees to let them stay for one night. Unknown to Tallulah, Margo is struggling with her own marital problems after her ex-husband Stephen has left her for a man, Andreas, and is pressing Margo to finalize their divorce. While Tallulah and Maddy stay with Margo, the three of them bond; Tallulah reveals her fears of forming relationships and Margo admits to having trouble letting go. However, Tallulah becomes increasingly aware that the authorities are looking for her and Maddy. Meanwhile, a distressed Carolyn is questioned by a social worker, who notes that Carolyn has only expressed concern for herself so far instead of her missing child. Frustrated with their questioning, Carolyn leaves the hotel to distract herself and discovers that her husband has cancelled all her credit cards, much to her fury. During a lunch with Stephen and Andreas, Margo defends Tallulah when Stephen begins to aggressively question Tallulah's relationships with Nico and Maddy. Margo lashes out at Stephen about their marriage and the deceit involved, pointing out that when all their friends supported Stephen, Margo had been left alone to reconcile the changes in her life and losing the family she loved. On their way back to Margo's apartment, Tallulah and Carolyn notice one another as the latter goes by in a cab. Just before Carolyn catches up to them, Tallulah narrowly escapes with Maddy and Margo via the subway. When Margo demands to know why Tallulah ran, an argument ensues and Tallulah runs off with a feverish Maddy to a pier that Nico had once told Tallulah was his favorite place. Nico arrives, having finally returned to his mother in New York City. Taking Maddy to the hospital, Nico devises a plan to allow Tallulah to escape. At Margo's apartment, Carolyn and the police arrive after a tip from Stephen and Andreas, who recognized Tallulah from a newspaper article reporting Maddy's abduction. Carolyn admits to Margo that she did not want to be a mother and feels no maternal instinct, despite loving her daughter; Margo comforts her. At a subway station, Tallulah calls Margo to apologize for involving her, and the police trace the call. Tallulah tries to get on the subway in order to flee, but instead returns to Maddy and Nico at the hospital. The police, Carolyn, and Margo arrive at the hospital, where an emotional Tallulah accuses Carolyn of not wanting Maddy. After a tearful Carolyn tells her that she does want her child, Tallulah reluctantly hands Maddy back to her and is arrested by the police. As Tallulah is taken away, Margo promises to help her however she can. When Detective Richards facetiously asks Tallulah if she has a habit of taking children into protective custody, Tallulah says nothing and smiles ruefully. Some time later, Margo wanders through Central Park before lying in the grass, recalling her conversation with Tallulah about letting go. Margo starts floating away happily, but then appears frightened and grabs a tree branch.

Frank Darbo, a devoutly religious short-order cook, recalls his only two good memories from an otherwise disappointing life: marrying his wife Sarah and pointing a police officer in the direction of a man who snatched a woman's purse. He immortalizes these events in two crayon drawings hung on his wall for inspiration. Sarah, a recovering drug addict, has left him for Jacques, a charismatic strip club owner and drug lord who gets her hooked on drugs again. Frank sinks into depression and has a vision wherein he is touched by the finger of God and meets the Holy Avenger, a superhero from a Christian network TV show who tells Frank that God has chosen him for a very special purpose. Frank believes that God has chosen him to become a superhero and goes to a local comic book store for inspiration. His claim that he is designing a new superhero is met with enthusiastic appreciation from the young store clerk, Libby, and he creates a superhero costume before assuming the identity of the "Crimson Bolt". Lacking superhuman abilities, he deals with injustice in his own way, using a pipe wrench to savagely beat people such as thieves, drug dealers, child molesters, and a man who simply cuts in line at the movies. The Crimson Bolt soon becomes a media sensation, initially viewed as a violent psychopath, but he begins to gain public appreciation after the criminal backgrounds of many of his victims come to light. Frank later attempts to rescue Sarah at Jacques' house, but Jacques' thugs recognize him under the costume and shoot him in the leg as he flees while climbing over a fence. A wounded Frank goes to Libby for help. Libby persuades Frank to let her become the Crimson Bolt's "kid sidekick", calling herself "Boltie" and designing a costume of her own. She proves to be more unhinged than Frank, using her superhero guise to nearly kill a man who possibly vandalized her friend's car, and Frank decides to let her go but changes his mind when she rescues him from some of Jacques' thugs at a gas station. Libby soon becomes enamored with Frank, but he turns down her advances, insisting he is still married. Arguing that the rules are different when they are using their superhero identities, Libby rapes Frank while the two are in costume and later claims to have been suffering from sexsomnia. Frank runs to the bathroom and vomits, encountering a vision of Sarah in the toilet. He decides to rescue her from Jacques once and for all. Armed with guns, pipe bombs, and bulletproof vests, Frank and Libby sneak into Jacques' ranch and kill the first few guards they encounter. Frank is shot in the chest and saved by his bulletproof vest, but Libby is shot in the head and killed. Devastated, Frank furiously slaughters all of Jacques' thugs. Inside, Jacques shoots Frank, but Frank gains the upper hand and stabs Jacques to death as a horrified Sarah watches. Frank takes Sarah home and she stays with him for a few months, which Frank surmises is "out of a sense of obligation" for saving her life. One day, Frank returns home to find Sarah has left him again. This time, she overcomes her addiction and uses her experiences to help others with similar problems. She marries a man named Patrick and has four children. Frank is convinced that her children will change the world for the better. Frank, content and living alone with a pet rabbit, looks at his wall of happy memories. The wall is now covered with pictures of his experiences from his time spent with Libby and pictures of Sarah's children, who call him "Uncle Frank". He gazes at Libby's picture as a tear runs down his cheek.

In New York City, a breaking news report informs the world that a mission to stop an incoming 70-mile-wide asteroid known as "Matilda" has failed and that it will make an impact in three weeks, destroying all life on Earth. Dodge Petersen and his wife, Linda, listen to the broadcast parked on the side of the road. When he expresses indifference, she looks disgusted and abandons both the vehicle and their marriage. Dodge stops going to his job at an insurance company where one of his co-workers has killed himself. He also attends an end-of-the-world party at the house of his best friend, where he politely avoids offers of heroin and the amorous intentions of both a stranger and his best friend's wife (on the latter, he says he cannot cheat with a married woman, but she points out that marriage means nothing now that civilization is going to end). A drunk man tells him he has never bedded so many women as now nobody cares about getting pregnant or catching diseases. At home, Dodge reminisces about his high school sweetheart, Olivia and notices his British neighbor Penny crying on the fire escape. Penny just broke up with her boyfriend Owen over him making her miss her last opportunity to see her family in England. At her apartment, Penny gives Dodge three years' worth of his mail that was incorrectly delivered to her and, in the process, unwittingly tells him that his wife was having an affair. Dodge storms off into the night, guzzling codeine -laced cough syrup and window cleaner in a suicide attempt. Dodge wakes up in a park, with a dog tethered to his foot and a note on his sweater reading "Sorry", which becomes the dog's name. Dodge takes Sorry home, opens the old mail, and is surprised to discover a three-month-old letter from Olivia, which explains that he was "the love of her life". Later, a riot breaks out in their neighborhood. Dodge and Penny abandon the self-centered Owen amid the rioters, with Dodge explaining to Penny that he knows someone who could fly her to England if she helps him find Olivia. She agrees, and they set off with Sorry for Dodge's hometown in Delaware. Along the way, Dodge and Penny run out of gas, witness the bizarre death of suicidal motorist Glenn whose plan to pay an assassin to kill him without warning pays off, see the beginning of an orgy at a chain restaurant but leave hurriedly before the frenzied sex begins, have sex themselves in a pick-up truck, and spend a night in jail. They get a ride to Camden, New Jersey, where they meet Penny's ex-boyfriend, Speck, who is prepared for the apocalypse with a well-stocked underground bunker. Speck has a working satellite phone and lets Penny contact her family. Penny and Dodge borrow a car from Speck and eventually make it to Olivia's family home. They walk up to the door of the home but find no one home and then spend the day together; they realize a mutual affection. Penny discovers a letter from Olivia to her parents, which reveals her address. Penny and Dodge drive to Olivia's home, where Dodge leaves a letter for Olivia. Later, they go to the house of the man who Dodge promised could take Penny to England. The man turns out to be his estranged father, Frank. After making amends with Frank, Dodge puts a sleeping Penny into his father's plane, whispering to her that she is the real love of his life. Frank and Penny depart, leaving Dodge behind. After one final news broadcast reveals that Matilda will make an impact one week earlier than originally reported, meaning there is less than a day left, Dodge takes refuge in Penny's apartment and awaits his imminent death; she unexpectedly returns, upset that he allowed her to leave. They lie in bed and comfort each other as they feel the tremor of the asteroid's impact. Penny regrets not having met Dodge sooner, while he assures her that their meeting had been opportune. Penny smiles as everything fades to white.