In 1858 Texas, several male African American slaves are being "driven" by the Speck Brothers, Ace and Dicky. Among the shackled slaves is Django, sold off and separated from his wife, Broomhilda. The Speck Brothers are stopped by Dr. King Schultz, a German ex-dentist and bounty hunter from Düsseldorf. Schultz asks to buy one of the slaves, but while questioning Django about his knowledge of the Brittle Brothers, for whom Schultz is carrying a warrant, he irritates Ace, who aims his shotgun at Schultz. Schultz quickly kills Ace and leaves Dicky at the mercy of the other newly freed slaves, who kill him. Since Django can identify the Brittle Brothers, Schultz offers Django his freedom in exchange for his help in tracking them down. Django discovers Schultz is a bounty hunter, as Schultz kills an outlaw named Willard Peck, who was posing as the Sheriff in a small town. Schultz and Django then track the Brittle Brothers down, leading them to a plantation in Tennessee. Django shoots dead the first brother, brutally whips the second before shooting him too, while Schultz kills the third brother. After getting out of it by producing the warrant for their capture “dead or alive”, they then ambush and kill the plantation owner who leads a group of lynchers to murder them in revenge. Django partners with Schultz through the winter and becomes his apprentice, and Schultz discovers Django's natural ability with gunslinging. Schultz explains that, being the first person he has ever given freedom to, he feels responsible for Django and is driven to help him in his quest to rescue Broomhilda. Django, now fully trained, collects his first bounty, keeping the handbill as a good luck charm. In Mississippi, Schultz uncovers the identity of Broomhilda's owner: Calvin Candie, the charming but brutal owner of the Candyland Plantation, where black slaves are forced to fight in wrestling deathmatches called " Mandingo fights". Schultz, expecting Candie will not sell Broomhilda if they ask for her directly, plots to feign interest in purchasing one of Candie's prized fighters, offer to purchase Broomhilda on the side for a reasonable sum, then take her and escape before the Mandingo deal is finalized. Schultz and Django meet Candie at his gentleman's club in Greenville and submit their offer. His greed tickled, Candie invites them to Candyland. After secretly briefing Broomhilda on the plan, Schultz claims to be charmed by the German-speaking Broomhilda and offers to buy her after arranging to buy a fighting slave. During dinner, Candie's staunchly loyal head house slave, Stephen, becomes suspicious. Deducing that Django and Broomhilda know each other and that the sale of the Mandingo fighter is just a misdirection, Stephen alerts and privately admonishes Candie on his greed. Candie is humiliated at being fooled by a black man, but he contains his anger long enough to theatrically display his knowledge of phrenology which he uses to justify white superiority and black inferiority. Candie's bodyguard suddenly bursts into the room with his shotgun trained on the two bounty hunters; Candie furiously threatens to kill Broomhilda if Schultz does not pay the complete bid amount, and taunts him by demanding a formal handshake to finalize the deal before he leaves. Tired of his arrogance and angered by his brutality, Schultz fatally shoots Candie with a concealed derringer and his bodyguard kills him in turn. Django grabs the bodyguard’s revolver and kills him to avenge Schultz, and after a violent shootout, in which the Candies’ lawyer is also killed along with several white overseers, Django is forced to surrender when Broomhilda is taken hostage at gunpoint. The next morning, Stephen tells Django that he will be sold to a mine where he will labor for the rest of his life. En route to the mine, Django proves to his dim-witted Australian escorts that he is a bounty hunter by showing them the handbill from his first kill. He convinces them that there is a large bounty for outlaws who are hiding at Candyland, and promises that they would receive most of the money. The escorts release him and give him a pistol, and he kills them before stealing a horse and leaving for Candyland. Django returns to the plantation and kills the slave trackers to avenge a slave they had torn apart by dogs and to ensure they will not be sent after him. He takes Broomhilda's freedom papers from Schultz's pocket, bidding his friend and mentor a final farewell before freeing Hildi from a nearby cabin. When Candie's mourners return from his burial, Django kills Candie's few remaining henchmen and his sister Lara, releases the two remaining house slaves, and kneecaps Stephen. Django then ignites dynamite that he has planted throughout the mansion. He and Broomhilda watch from a distance as the mansion explodes, killing Stephen, before they ride off together.

William Blake, an accountant from Cleveland, Ohio, rides by train to the frontier company town of Machine to take up a promised accounting job in the town's metal works. During the trip, the train fireman warns Blake against the enterprise. Arriving in town, Blake notes the hostility of the townsfolk towards him. He then discovers that the position has already been filled, and John Dickinson, the ferocious owner of the company, drives Blake from the workplace at gunpoint. Jobless and without money or prospects, Blake meets Thel Russell, a former prostitute who sells paper flowers. He lets her take him home. Thel's ex-boyfriend Charlie surprises them in bed, shoots at Blake, and accidentally kills Thel when she shields Blake with her body. The bullet passes through Thel and wounds Blake, who kills Charlie with Thel's gun before climbing out the window and fleeing the town on Charlie's horse. Company owner Dickinson is Charlie's father and hires three killers — Cole Wilson, Conway Twill, and Johnny "The Kid" Pickett — to bring Blake back "dead or alive". Blake awakens to find a large Native American man trying to dislodge the bullet from his chest. The man, calling himself Nobody, reveals that the bullet is too close to Blake's heart to remove, rendering Blake effectively a walking dead man. When he learns Blake's full name, Nobody decides Blake is a reincarnation of William Blake, the eighteenth- and nineteenth-century English poet, whom he idolizes, but of whom Blake is admittedly ignorant. He decides to care for Blake and to use Native methods to help ease him into death. Blake learns of Nobody's past, marked by prejudice from Euro-Americans who objected to his Indigenous ancestry, and equally from Native Americans who objected that his mother and father were from two opposing tribes, Piikáni and Apsáalooke, respectively. As a child, English soldiers abducted and brought him to Europe as a model savage. He was briefly educated before returning home, where his stories of the white man and his culture were laughed off by fellow Native Americans. They thus dub him Xebeche: "He who talks loud, saying nothing". Nobody resolves to escort Blake to the Pacific Ocean to return him to his proper place in the spirit world. Blake and Nobody travel west, leaving a trail of dead and encountering wanted posters announcing growing bounties for Blake's death or capture. Nobody leaves Blake alone in the wild when he decides Blake must undergo a vision quest. On his quest, Blake kills two U.S. Marshals, experiences visions of nature spirits, and grieves over the remains of a dead fawn his pursuers accidentally kill. He paints his face with the fawn's blood and rejoins Nobody. Meanwhile, the most ferocious member of the bounty hunter posse, Cole Wilson, has killed his comrades (eating one of them) and continued his hunt alone. At a trading post, a bigoted missionary identifies Blake and attempts to kill him but instead dies at Blake's hands. Shortly after, Blake is shot again, and his condition rapidly deteriorates. Nobody hurries to take him by the river to a Makah village and persuades the tribe to give him a canoe for Blake's ship burial. Delirious, Blake trudges through the village, where the people pity him, before he collapses from his injuries. He awakens in a canoe on a beach wearing a Native American funeral dress. Nobody bids Blake farewell and then pushes the canoe out to sea. As he floats away, Blake sees Cole approaching Nobody. Too weak to cry out, he can only watch as the two shoot and kill each other. Looking up at the sky one last time, Blake dies as his canoe drifts out to sea.

The plot consists of four acts, which are presented in anachronic order. The chronological order is Acts 3 (Genesis), 2 (Exodus), 1 (Revelation), and 4 (Retribution). So, after the first act, Revelation, the following acts are what happened before and the fourth act is chronologically the last. 1. Revelation Elizabeth "Liz" Brundy lives in the Old West with her husband Eli and their two children: Matthew, Eli's son from a previous marriage, and daughter Samantha, called Sam. Liz works as a midwife who can hear but is mute, and so communicates through sign language. One day, a new Preacher, known as "The Reverend", hosts a session at the local church, and the moment that Liz hears his voice, she seems to recognize him and is terrified by his appearance. Later that day, Liz is forced to choose between delivering a baby safely or saving its mother; she chooses to euthanise the baby and save the mother, without telling her until after the procedure is finished. Afterwards, Nathan, the husband of the formerly-pregnant woman, blames Liz. That night, Nathan drunkenly shows up at Eli and Liz's house, violent and threatening; Nathan claims Liz is responsible for his son's death. In the middle of the fight, the Reverend shows up and tells him to leave. He then goes into Eli's house and has a mysterious talk with Liz, saying she is guilty of the murder of Nathan's son and must be "punished". As Eli overhears some of the conversation, the Reverend leaves the house. Eli's sheep are found dead the next morning, and he seeks out Nathan, who has since disappeared. Liz later sneaks off at night to murder the Reverend, but finds her daughter's doll in the Reverend's bed instead. Meanwhile, the Reverend disembowels Eli, and leaves him to die. As he succumbs to his wounds, Eli tells Matthew to take the family up into the mountains to his father, before the boy mercy kills him. Liz and the children flee the farm. 2. Exodus A young girl named Joanna, walking through the desert, is picked up and nursed by a traveling Chinese family. In the mining town of Bismuth, Joanna is sold to a brothel owned by Frank. She is protected by Sally, a prostitute, until Sally is hanged for shooting a violent customer; another prostitute, Elizabeth, then protects Joanna in the aftermath of Sally's hanging. However, when Elizabeth bites the tongue of an abusive customer, her tongue is cut off as punishment. Joanna teaches Elizabeth sign language from a book the doctor gave her. Elizabeth plans to sneak out of Bismuth to start a new life, and arranges through a marriage broker to marry Eli. The Reverend comes to the brothel, recognizes Joanna, and proceeds to violently attack her. Elizabeth tries to save Joanna but is murdered by the Reverend with Joanna slashing his throat in retaliation. She runs away, cutting off her own tongue and taking Elizabeth's place with Eli. 3. Genesis In the desert, two badly wounded men, Samuel and Wolf, are the last survivors in a dispute over gold that has left several other men dead. They depart on a single horse. Joanna lives with her mother, Anna, and father, revealed to be the Reverend himself. He is strictly religious and is often cruel and abusive towards his family. Samuel and Wolf collapse at the farm and Joanna secretly cares for them. Anna confronts the Reverend when she realizes he lusts after their daughter, so he beats and humiliates her by placing a scold's bridle on her head. In response, Anna commits suicide in full view of the church congregation. The next day the Reverend takes Joanna to church and starts to perform a wedding ceremony between himself and his daughter. Samuel tries to rescue her, but the Reverend murders him. Her father whips Joanna and rapes her. In the morning she runs off. 4. Retribution Matthew is shot by the Reverend as he follows Liz to her father-in-law's place in the mountains. He murders her father-in-law and tells Liz he will beat and rape her daughter, but Liz murders him instead. Sometime later, after Liz has turned Eli's place into a sawmill, Nathan arrives to arrest her. The Reverend had sent him to Bismuth where he became a deputy and then sheriff. Having found a wanted poster of Elizabeth Brundy (the woman without a tongue who killed Frank before she saved Liz/Joanna), Nathan has come to arrest her (Liz). As Nathan is escorting her onto a ferry, with a last look at her daughter playing on the shore, Liz throws herself in the lake and drowns. Her daughter Sam, now a grown woman with a child of her own, remembers her well.

In Pamplona, Spain, middle-aged friends Mitch Robbins, Ed Furrilo and Phil Berquist participate in the running of the bulls. As they fly back in the airplane, Mitch tells Ed he is getting fed up with their road trips. A year later, back home in New York City, Mitch realizes he and his friends use adventure trips as escapism from their boring lives, since he is disillusioned with his radio advertising sales job, Phil is trapped in a loveless marriage to his shrewish wife Arlene while managing a supermarket owned by his father-in-law who bullies him, and Ed is a successful and outgoing sporting goods salesman who recently married Kim, a significantly younger woman, but is unwilling to fully settle down. At Mitch's 39th birthday party, Phil and Ed give Mitch a trip for all three to go on a two-week cattle drive from New Mexico to Colorado. Phil's 20-year-old employee Nancy unexpectedly arrives at the party and announces she tested positive in a pregnancy test, causing Arlene to walk out after a fight. Mitch's wife, Barbara, insists he go on the cattle drive to find his smile again. In New Mexico, the trio meet ranch owner Clay Stone and their fellow cattle drivers: brothers and ice cream company founders Barry and Ira Shalowitz, young and attractive Bonnie Rayburn, father-son dentists Ben and Steve Jessup, ranch hands Jeff and T.R., and Cookie the cook. Mitch confronts Jeff and T.R. when they begin sexually harassing Bonnie. Trail boss Curly intervenes, though he also humiliates Mitch. During the drive, Mitch accidentally causes a stampede which destroys the camp. While searching for stray cows, Mitch discovers Curly has a kind and wise nature beneath his gruff exterior. Curly encourages Mitch to discover the "one thing" in his life that is most important to him. Along the way, Mitch helps deliver a calf from a dying cow. Mitch names the calf Norman. Shortly after, Curly suffers a fatal heart attack, leaving the drive under Jeff and T.R.'s control. Cookie gets drunk and inadvertently sends the chuck wagon over a cliff, breaking his legs in the process. After the Jessups leave to take Cookie to a nearby town (being more qualified because of their medical training in dentistry), Jeff and T.R. become intoxicated with Cookie's secret stash. A fight ensues when they threaten to kill Norman and assault Mitch. Phil and Ed intervene, and Phil holds Jeff at gunpoint, which unleashes his pent-up emotions. Soon after, Jeff and T.R. abandon the group. Bonnie and the Shalowitzes continue on to the Colorado ranch, while Ed and Phil remain behind to finish the drive. Mitch also leaves but soon returns to rejoin his friends. After braving a heavy storm, the trio drives the herd to Colorado. When Norman nearly drowns as the herd crosses a river, Mitch acts to save him. Both are swept down current, but Phil and Ed rescue them. They safely reach the Colorado ranch. When Stone offers to reimburse everyone's fee, the Jessups prefer returning the herd to New Mexico. However, Clay reveals he is selling the herd to a meat-packing company. Mitch, Phil, and Ed initially believe they saved the cattle for nothing, but decide to use their experience to help re-evaluate their lives. The men return to New York City. Mitch, a happier man, reunites with Barbara and their two children Holly and Danny; he has also brought Norman home as a pet(he'll later put him in a petting zoo). Phil, having learned earlier Nancy was not pregnant, begins a relationship with Bonnie. Ed intends to start a family with Kim. Mitch is ready to restart his life with a new stance.