In 1858 Texas, brothers Ace and Dicky Speck drive a group of shackled black slaves on foot. Among them is Django, sold off and separated from his wife Broomhilda von Shaft, a house slave who speaks German and English. They are stopped by Dr. King Schultz, a German dentist-turned-bounty hunter seeking to buy Django for his knowledge of the three outlaw Brittle brothers, overseers at the plantation of Django's previous owner and for whom Schultz has a warrant. When Ace refuses to sell Django to Schultz and levels his gun at him, Schultz kills him and shoots Dicky's horse in order to pin him to the ground. Schultz insists on paying a fair price for Django before leaving the other slaves to kill Dicky. Schultz offers Django his freedom and $75 in exchange for help tracking down the Brittles.

Django and Schultz kill the Brittle brothers at Spencer "Big Daddy" Bennett's Tennessee plantation. Bennett lets Django and Schultz leave due to the warrant, but later tries to attack them with a posse. Schultz ambushes the posse with explosives and Django kills Bennett. Feeling responsible for Django, Schultz agrees to help him find and rescue Broomhilda. They return to Texas where Django collects his first bounty, keeping the handbill as a memento. He and Schultz rack up several bounties before spring, when they travel to Mississippi and learn that Broomhilda's new owner is Calvin J. Candie, the charming but cruel owner of the Candyland plantation, where slaves are forced to wrestle to the death in brutal "Mandingo" fights. Schultz and Django hatch a plan: deciding that Candie will price Broomhilda beyond their reach if they try to buy her upfront, they will instead offer $12,000 (equivalent to $376,000 in 2021) for one of his best fighters as a pretext to acquiring Broomhilda for a nominal sum. They meet Candie at his gentlemen's club and make the offer. Intrigued, Candie invites them to Candyland. En route, the group encounters Candie's slave trackers who have cornered D'Artagnan, an escapee Mandingo fighter. Schultz attempts to save him, but Django intervenes to prevent him from blowing their cover. Candie has the trackers' dogs maul D'Artagnan to death, visibly upsetting Schultz.