In 1882, in the town of Old Stump, Arizona, a cowardly sheep farmer named Albert Stark (Seth MacFarlane) is dumped by his beloved girlfriend Louise (Amanda Seyfried) as a result of his withdrawal from a gunfight. He prepares to leave for San Francisco, believing that the frontier holds nothing for him. Meanwhile, infamous outlaw Clinch Leatherwood (Liam Neeson) robs and kills an old prospector (Matt Clark) for a gold nugget. He orders his right-hand man Lewis (Evan Jones) to escort his wife Anna (Charlize Theron) to Old Stump to lie low while he continues his banditry. Lewis and Anna arrive in Old Stump under the guise of two siblings intending to build a farm, but Lewis is arrested after shooting the Pastor's (John Aylward) son (Dylan Kenin) in a saloon. During the ensuing brawl, Albert saves Anna from being crushed to death by two of the brawlers, and the two become good friends. They attend a County Fair where Louise's new boyfriend, the foppish Foy (Neil Patrick Harris), challenges Albert to a shooting contest. Albert is defeated, but Anna steps up and defeats Foy. Foy mocks Albert, who angrily challenges Foy to a duel in a week's time.
Anna teaches Albert how to shoot. During a barn dance the night before the duel, Anna slips Foy a Mickey. After leaving the dance, Albert and Anna kiss before heading home. Upon breaking out of jail and murdering the sheriff, Lewis witnesses the kiss and reports it to Clinch. On the day of the duel, Foy arrives late and goes into convulsions from the laxative he had unknowingly imbibed. Albert, who has decided that Louise is not worth the trouble, once again forfeits the duel. He retires to the saloon, but Clinch arrives and demands to know who kissed his wife. When no one comes forward, Clinch shoots a nearby cowboy (Ryan Reynolds). He reveals that Anna is his wife and threatens to continue killing unless his wife's lover duels him at noon the next day. Clinch later forces Anna to reveal Albert's name and then prepares to have sex with her, but she knocks him unconscious and escapes.
Anna returns to Albert's farm where he shouts at her. Clinch pursues Anna to the farm; Albert helps her escape, then escapes himself. While fleeing, he is captured by a tribe of Apache Indians, who threaten to burn him alive. The Indians spare him when he reveals that he can speak their language. They give him a bowl of peyote, which sends him flashing back to his birth and through agonizing events of his childhood before making him realize that he loves Anna. Meanwhile, Clinch recaptures Anna in town, in front of Edward's (Giovanni Ribisi) house. Albert returns to Old Stump and confronts Clinch. He wounds Clinch with a bullet poisoned with rattlesnake venom before his own gun is shot out of his hand, but he manages to stall until Clinch fatally succumbs to the poison. Louise attempts to win back Albert, but he rejects her and instead happily enters a relationship with Anna. Albert also receives a bounty for killing Clinch and uses the money to buy more sheep.
Later at the Fair, the proprietor of a racially charged shooting game "Runaway Slave" asks who would like to take a shot. Django (Jamie Foxx) steps up and shoots the man while commenting that "people die at the fair".