In 1877, bounty hunter and Civil War veteran Major Marquis Warren is heading to Red Rock, Wyoming. After his horse gives out he hitches a ride on a stagecoach driven by O.B.; aboard is bounty hunter John Ruth, handcuffed to fugitive Daisy Domergue, whom he is taking to Red Rock to be hanged. While Ruth is suspicious that he found a fellow bounty hunter on the road he is persuaded to let him ride with him as Ruth and Warren had previously bonded over Warren's personal letter from Abraham Lincoln. Lost-Causer Chris Mannix, Red Rock's new sheriff, is also found on the road causing Ruth to be even more suspicious that Mannix and Warren might be working together to take his bounty. He is eventually persuaded they are not as Mannix is deeply racist and Warren is a black man.
The members of the stagecoach seek refuge from a blizzard at Minnie's Haberdashery lodge. While there they are greeted by Señor Bob, a Mexican, who says Minnie is away and he has been left in charge. Other lodgers are Red Rock's new hangman, "Oswaldo Mobray"; cowboy Joe Gage; and Sanford Smithers, a Confederate general traveling to hold a funeral for his son who disappeared in mysterious circumstances. Suspicious, Ruth disarms all but Warren.
Mannix surmises Warren's Lincoln letter is false, and Warren, acknowledges the forged letter buys him leeway with whites. Warren leaves a gun next to Smithers and provokes him by claiming that he knows Smithers' son who attempted to claim a bounty on Warren at one time leading Warren to sexually assault and then murder him. When Smithers reaches for the gun, Warren shoots and kills him in revenge over executions of black prisoners of war at the battle of Baton Rouge.
At the same time, someone poisons the coffee. Ruth and O.B. drink it, which kills O.B. while the poisoned Ruth attacks Domergue who then kills him with his own gun. Warren disarms Domergue, leaving her shackled to Ruth, and holds the others at gunpoint. He is joined by Mannix, whom Warren trusts because he nearly drank the poisoned coffee.
Discovering the chair usually occupied by Sweet Dave is stained with blood and revealing that Minnie hated Mexicans and would never leave the Haberdashery in the care of one, Warren deduces that Bob killed the owners and promptly executes him. When Warren threatens to execute Domergue, Gage admits he poisoned the coffee. An unknown man, hiding in the cellar below, shoots upward through the floorboards, hitting Warren in the groin. Mobray shoots Mannix, who returns fire, wounding Mobray.
A flashback reveals that hours earlier, Bob, Mobray, Gage, and the unknown man: Domergue's brother Jody, arrive at the lodge. They murder Minnie and five others, leaving only Smithers. Jody tells him they plan to rescue Domergue, and will spare him if he keeps quiet. They dispose of the bodies and hide the evidence. As Ruth's stagecoach arrives, Jody hides in the cellar.
In the present, Mannix and Warren, both seriously wounded, hold Domergue, Gage, and Mobray at gunpoint. When they threaten to kill her, Jody surrenders but is executed by Warren. A broken-hearted Domerque nevertheless offers a deal to Mannix. She claims 15 of her brother's men are waiting in Red Rock to rescue her in case the rescue at Minnie's fails. If Mannix kills Warren and allows her to escape, the gang will spare him and allow him to collect the bounty on Mobray who is close to death.
Warren shoots Domergue and Mobray, killing Mobray. Gage draws a revolver, but is shot dead by both Mannix and Warren. Warren tries to shoot Domergue, but is out of bullets. He asks Mannix for his gun but Mannix refuses it, giving Domergue a further opportunity to make a deal with him. She once again tells Mannix she will allow him to walk free and points out that he will be unable to collect on his bounties and face the 15 men waiting for him at Red Rock. Despite her convincing pitch Mannix rejects her offer as he does not believe Domergue's claims about the 15 men. While berating Domergue for thinking she could fool him Mannix faints from blood loss. Domergue hacks off Ruth's handcuffed arm and frees herself while the still injured Warren watches helplessly. When Domergue goes for a gun Mannix regains consciousness and shoots her. When Mannix attempts to kill Domergue with a bullet to the head Warren persuades him to hang Domergue from the rafters in honor of Ruth who was known as "The Hangman" for always bringing his bounties in alive so they could be hung. As they lie dying, Mannix reads aloud Warren's Lincoln letter, complimenting his attention to detail.
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