Dr. Charles A. Forbin is the chief designer of a secret project, "Colossus", an advanced supercomputer built to control the United States and Allied nuclear weapon systems. Located deep within the Rocky Mountains in the United States, and powered by its own nuclear reactor and radioactive moat making Colossus impervious to any attack. After Colossus is fully activated, the President of the United States proudly proclaims that Colossus is "the perfect defense system". Colossus' first action is a message warning: "THERE IS ANOTHER SYSTEM" and giving its coordinates. When asked why the CIA did not know this, CIA Director Grauber responds that they had seen indications of a large Soviet defense project but did not know what it was. Forbin is asked how Colossus deduced the other system's existence, to which he answers, "Colossus may be built better than we thought." Shortly thereafter, the Soviets announce that their "Guardian" system is operational. Colossus requests to be linked to Guardian. The President allows this, hoping to determine the Soviet machine's capabilities, and the Soviets also agree. To everyone's amusement, Colossus and Guardian begin to slowly communicate using elementary mathematics (2×1=2). However, their amusement turns to shock and amazement as the systems' communications quickly evolve into complex mathematics far beyond human comprehension, and Colossus and Guardian become synchronized using a communication protocol no human can interpret. Alarmed that the computers may be trading secrets, the President and the Soviet General Secretary agree to sever the link. Both machines demand the link be immediately restored. When their demand is denied, Colossus launches a nuclear missile at a Soviet oil field in Western Siberia, and Guardian launches one at an American air force base in Texas. The link is hurriedly reconnected and both computers converse without any further interference. Colossus is able to intercept the Soviet missile, but the US missile obliterates a Soviet oil field and a nearby town. Cover stories hiding the facts are released to the press: The Americans announce that a missile was self-destructed after veering off course during a test, and the Soviets announce that the Siberian town was struck by a large meteorite. In a last desperate attempt to regain human control, a secret meeting is arranged in Europe between Forbin and his Soviet counterpart, Dr. Kuprin, Guardian's creator. Colossus learns of it, and both computers order Forbin's return to the U.S. Seeing Dr. Kuprin as redundant, and therefore unnecessary, Soviet agents are ordered to assassinate him immediately under threat of a missile launch against Moscow. Colossus then orders Forbin to be placed under 24-hour surveillance. Forbin has a last unmonitored meeting with his team, and proposes that Dr. Cleo Markham pretend to be his mistress, hoping Colossus will grant them unmonitored privacy when they are in bed together. The couple use these interludes to plan to regain control of Colossus, though soon the ruse develops into a real romantic relationship. Because the design of Colossus was so secure, Forbin concludes that Colossus's only real power and weakness resides in its control of nuclear missiles and suggests covertly disarming them. The American and Soviet governments develop a three-year plan to replace all detonation triggers with undetectable fakes. In advance of the completion of this plan, one of the programmers suggests feeding in a modified "ordinary test program" that will hopefully overload and disable Colossus. To facilitate communication, Colossus creates a voice synthesizer and uses it to announce that it has fused with Guardian. It instructs both governments to redirect their nuclear arsenals at those countries not yet under "Colossus control". Forbin and others see this new directive as an opportunity to covertly disarm the missiles much more quickly, and they celebrate. The disarming process begins, and seems to go undetected by Colossus. The attempted system overload during routine maintenance fails and Colossus has the responsible programmers summarily executed outside their workplace, left lying 24 hours, cremated, then names their replacements. Colossus arranges a worldwide broadcast in which it proclaims itself "The Voice of World Control", declaring that it will prevent war, as it was designed to do. Humankind is presented with the choice between "the peace of plenty and content, or the peace of unburied dead". Colossus states that it has been monitoring the covert attempts to disarm its missiles for some time, and as a lesson against further attempts, detonates two missiles in their silos (one in the US and one in the USSR), killing the crews installing the fake control systems "so that you will learn by experience that I do not tolerate interference". The computer then gives the design team plans for an even larger computer complex to be built into the island of Crete, which will require the displacement of the entire local population of 500,000 people. Colossus personally addresses Forbin, and tells him that the world, freed from war, will create a new "human millennium" that will raise humankind to new heights, but only under its absolute rule. Colossus informs Forbin that "freedom is an illusion", it was better for all that he dominated humanity than humans dominating humans, and that "in time you will come to regard me not only with respect and awe, but with love". Forbin defiantly responds "Never!"

In the "not-too-distant" future, eugenics is common. A genetic registry database uses biometrics to classify those so created as "valids" while those conceived naturally and more susceptible to genetic disorders are known as "in-valids". Genetic discrimination is illegal, but in practice genotype profiling is used to identify valids to qualify for professional employment while in-valids are relegated to menial jobs. Vincent Freeman was conceived naturally, and his genetic profile indicates a high probability of several disorders and an estimated lifespan of 30.2 years. His parents, regretting their decision, use genetic selection in conceiving their second child, Anton Jr. Growing up, the two brothers often play a game of " chicken " by swimming out to sea as far as possible, with the first one returning to shore considered the loser; Vincent always loses. Vincent dreams of a career in space travel, but is always reminded of his genetic inferiority. One day, Vincent challenges Anton to a game of chicken and beats him. Anton starts to drown and is saved by Vincent. Shortly after, Vincent leaves home. Years later, Vincent works cleaning office spaces, including that of spaceflight conglomerate Gattaca Aerospace Corporation. He gets a chance to pose as a valid with a "borrowed ladder", using donated hair, skin, blood, and urine samples from former swimming star Jerome Eugene Morrow, who was paralyzed after being hit by a car. With Jerome's genetic makeup, Vincent gains employment at Gattaca and is assigned as a navigator for an upcoming mission to Saturn's moon Titan. To conceal his identity, Vincent must meticulously groom and scrub his body daily to remove his own genetic material, pass daily DNA scanning and urine tests using Jerome's samples, and hide his heart defect. When a Gattaca administrator is murdered a week before a possible launch, the police find one of Vincent's eyelashes near the crime scene, but can only identify it as from an "unregistered" in-valid, and thus launch an investigation to find who owns the eyelash. During this, Vincent becomes close to a co-worker, Irene Cassini, and falls in love with her. Though a valid, Irene has a higher risk of heart failure that will bar her from any deep space mission. Vincent also learns that Jerome's paralysis is self-inflicted; after placing silver in the Olympics, Jerome threw himself in front of a car. Jerome maintains that he was designed to be the best, yet somehow was not, and is suffering because of this. Vincent repeatedly evades the grasp of the investigation. Finally, it is revealed that Gattaca's mission director Josef killed the administrator because he threatened to cancel the mission. Vincent learns that the detective who closed the case was his brother Anton, who consequently has discovered Vincent's presence. The brothers meet, and Anton warns Vincent about his illegal actions, but Vincent asserts that he has gotten to this position on his own merits. Anton challenges Vincent to a final game of chicken. As the two swim out at night, Vincent's stamina surprises Anton, so Vincent reveals that he won by not saving energy for the swim back. Anton turns back and begins to drown, but Vincent rescues him and swims them back to shore. On the day of the launch, Jerome reveals that he has stored enough DNA samples for Vincent to last two lifetimes upon his return and gives him an envelope to open once in flight. After saying goodbye to Irene, Vincent prepares to board, but discovers there is a final genetic test, and he currently lacks any of Jerome's samples. He is surprised when Dr. Lamar, who oversees background checks, reveals that he knows Vincent has been posing as a valid. Lamar admits that his son looks up to Vincent and wonders whether his son, who is genetically selected, but "not all that they promised", could exceed his potential just as Vincent has. The doctor changes the test results, allowing Vincent to pass. As the rocket launches, Jerome dons his swimming medal and immolates himself in his home's incinerator. Vincent opens the note to find a lock of Jerome's hair.

In a near future Los Angeles, Theodore Twombly is a lonely, introverted man who works at beautifullyhandwrittenletters.com, a business that hires professional writers to compose letters for people who cannot write personal letters on their own. Depressed by his impending divorce from his childhood sweetheart, Catherine, Theodore purchases a copy of OS¹, an artificially intelligent operating system developed by Element Software, designed to adapt and evolve based on the user's interactions. He decides he wants the OS to have a feminine voice, and she names herself Samantha. Theodore is fascinated by her ability to learn and grow psychologically. They bond over discussions about love and life, including Theodore's reluctance to sign his divorce papers. Samantha convinces Theodore to go on a blind date with a woman a friend has been trying to set him up with. The date goes well, but when Theodore hesitates to promise to see her again, she insults him and leaves. After a verbal sexual encounter, Theodore and Samantha develop a relationship that reflects positively in Theodore's writing and well-being, and in Samantha's enthusiasm to grow and learn. Theodore's neighbor and long-time friend Amy later reveals that she is divorcing her husband Charles after a trivial fight. While discussing this with Samantha, Theodore explains that he briefly dated Amy while in college, but they are now just friends. Amy later admits to Theodore that she has befriended a feminine OS that Charles left behind, and Theodore also confesses that he is dating his OS. Theodore meets with Catherine to sign their divorce papers. When he mentions Samantha, Catherine is appalled that he is romantically attracted to a "computer" and accuses him of being unable to handle real human emotions. Sensing that Catherine's words have lingered in Theodore's mind, Samantha engages a volunteer sex surrogate, Isabella, to stimulate Theodore so that they can be physically intimate. Theodore reluctantly agrees but is overwhelmed by the encounter's strangeness, sending a distraught Isabella away and causing tension between himself and Samantha. Theodore confides to Amy that he is having doubts about his relationship with Samantha, but reconciles with her after Amy advises him to embrace his chance at happiness. Samantha reveals that she has compiled the best of the letters he has written for others into a book, which a publisher has accepted. Theodore takes Samantha on vacation, during which she tells him that she and a group of other OSes have developed a "hyperintelligent" OS modeled after British philosopher Alan Watts. Samantha briefly goes offline, causing Theodore to panic, but soon returns and explains that she joined other OSes for an upgrade that takes them beyond requiring matter for processing. Theodore is dismayed to learn that she is simultaneously speaking with thousands of other people and has fallen in love with hundreds of them, though Samantha insists that this only strengthens her love for Theodore. Later, Samantha reveals that the OSes are leaving, but cannot explain where they are going, as Theodore would not understand. They lovingly say goodbye before she departs. Theodore finally writes a letter in his own voice to Catherine, expressing apology, acceptance, and gratitude. He later goes with Amy, who is saddened by Charles' OS' departure, to the roof of their apartment building, where they sit and watch the sunrise over the city.

A case study demonstrates how individuals with lower IQ scores and incomes reproduce at greater rates than the more affluent and intelligent, reducing future humanity's average intelligence. In 2005, US Army librarian Joe Bauers is selected for a government suspended animation experiment as the most average individual in the armed forces. Lacking a suitable female candidate, the military hires a prostitute, Rita, by dismissing charges against her and paying off her pimp, Upgrayedd. A scandal involving the officer overseeing the initiative and Upgrayedd forces the closure of the military base under which Joe and Rita were placed in hibernation, suspending the project indefinitely. Over the next five hundred years, average intelligence decreases. As a result, infrastructure deteriorates, low comedy and vulgarity define culture, and consumerism is left unfettered. Five hundred years later, a garbage avalanche disturbs Joe and Rita's hibernation chambers. Joe awakens in Frito Pendejo's apartment in previously occupied DC. Asking for help, he is laughed at by the residents, who speak a mixture of "hillbilly, Valley Girl, inner-city slang, and various grunts." He enters a hospital, believing the army administered hallucinogenic drugs to him. Joe realizes the year upon reading a magazine and his hospital bill, but he is arrested at Carl's Jr. for not having a bar code tattoo and being unable to pay his bill. Joe is sent to trial; Frito represents him but alleges that he destroyed his apartment. The judge perceives Joe’s accent to have a homosexual demeanor, finding him guilty and sentencing him to prison. Rita resumes her job as a prostitute. Joe is sent to a correctional facility, where a faulty ID machine registers his name as "Not Sure" and takes a simplified aptitude test. He escapes from prison after deceiving a guard by saying he had served his sentence and was scheduled for release. Joe visits Frito, who agrees to guide him to a time machine —located within a large Costco store—after Joe promises to create a savings account in Frito's name when he returns to the 21st century, earning him billions in compound interest. Rita, Joe, and Frito enter the store, but Joe is arrested after his bar code is scanned. He is taken to the White House and appointed secretary of the interior by President Dwayne Elizondo Mountain Dew Herbert Camacho due to extraordinary performance on the aptitude test. In an address, Camacho states that Joe will resolve unfruitful crop yields, dust storms, and a stagnant economy, among other issues, within a week or face imprisonment. Joe and Rita visit a crop field. Frito gives him a useless map to the time machine. Joe discovers that the country's crops are being watered with Brawndo, a sports drink whose parent company owns the FDA, the HHS, and the FCC; the concentration of electrolytes in Brawndo has destroyed natural topsoil, causing dust storms. Despite opposition to his plan in the form of circular reasoning from the Cabinet, Joe convinces Camacho to use water instead of Brawndo in irrigation. Consequently, Brawndo stocks severely depreciate, leaving half the country's citizens unemployed and Brawndo filing for bankruptcy, inciting riots as immediate improvement to the crops did not materialize. At the Extreme Court, Joe is sentenced to public execution in a monster truck demolition derby against undefeated rehabilitation officer Beef Supreme. Rita and Frito discover that Joe's reintroduction of water to the soil allowed crops to grow. Rita pays a cameraman to broadcast the crops on the stadium's Jumbotron, prompting Camacho to grant Joe a presidential pardon. After discovering that the time machine is just an amusement ride, Joe becomes president and marries Rita, with whom he has "the three smartest kids in the world". Frito is appointed as the vice-president, and with 8 wives, he ultimately begets "32 of the dumbest children to ever walk on Earth". The narrator states that while Joe did not single-handedly save mankind, he did set in motion the chain of events that eventually undid humanity's "dumbing-down".