The film opens to eight men eating breakfast at a diner. Six of them wear matching suits and are using aliases: Mr. Blonde (Michael Madsen), Mr. Blue (Eddie Bunker), Mr. Brown (Quentin Tarantino), Mr. Orange (Tim Roth), Mr. Pink (Steve Buscemi), and Mr. White (Harvey Keitel). Among them is Los Angeles gangster Joe Cabot (Lawrence Tierney), and his son, "Nice Guy" Eddie Cabot (Chris Penn). Mr. Brown discusses his comparative analysis on Madonna's "Like a Virgin", Joe's senior moments involving his address book rankle Mr. White, and Mr. Pink defends his anti-tipping policy until Joe forces him to leave a tip for the waitresses.

After the opening credits, the action cuts to the interior of a speeding car. Mr. White, driving with one hand, is trying to comfort a hysterical Mr. Orange, who has been shot in the abdomen and is bleeding profusely. They arrive at an abandoned warehouse, later revealed to be the rendezvous point for the armed robbery they have just committed. Mr. White leaves Mr. Orange on the warehouse floor when Mr. Pink appears, angrily suggesting that their robbery of a jeweler, orchestrated by Joe Cabot, was a police-setup. Mr. White reveals that Mr. Brown has been shot and killed by the police, and the whereabouts of Mr. Blonde and Mr. Blue are unknown to both. A flashback is played, revealing more of Mr. White's long-time friendship with Joe Cabot.

The two men discuss the actions of the sociopathic Mr. Blonde, who murdered several civilians after the jeweler's alarm had triggered; the police arrived at the scene remarkably soon after the alarm was activated. Mr. White is angered about Cabot's decision to employ such a psychopath and agrees about the possibility of a setup, while Mr. Pink confesses to having hidden the jeweler's diamond cache in a secure location. However, they violently argue about whether or not to take the unconscious Mr. Orange to a hospital when Mr. White reveals that he had told the former his true first name. Mr. Blonde, who has been watching them from the shadows, steps forward and ends their Mexican standoff, telling them not to leave the rendezvous as Nice Guy Eddie is on his way. Mr. Blonde takes them outside to his car and opens the trunk to reveal he captured a police officer named Marvin Nash (Kirk Baltz). A second flashback reveals that Mr. Blonde became involved in Cabot's heist team because of his friendship and loyalty to Eddie.

The three men torture the officer until a furious Eddie arrives at the warehouse. After berating the men over the carnage and incompetence displayed at the heist, he orders Mr. Pink and Mr. White to assist him retrieve the stolen diamonds and dispose of the hijacked vehicles, while ordering Mr. Blonde to stay with Nash and the dying Mr. Orange. Nash states that he has been a police officer for eight months and is ignorant as to a possible setup. He then pleads with Mr. Blonde to release him without further incident. However, after the others leave, Mr. Blonde confesses to enjoying torture, at which he turns on the radio and dances to "Stuck in the Middle With You" by Stealers Wheel before severing Nash's ear with a straight razor. He then retrieves a large gasoline can from the trunk of his car and is about to set Nash alight when Mr. Orange, having regained consciousness, produces a handgun and repeatedly shoots Mr. Blonde. Mr. Orange tells Nash that he is actually an undercover police detective named Freddy Newandyke, and reassures him that a massive police force is in position several blocks downtown waiting for Joe Cabot to arrive.

A series of flashback scenes detail Mr. Orange's involvement in an undercover operation to capture Cabot, culminating in a sequence depicting the death of Mr. Brown as he attempts to drive Mr. White and Mr. Orange away from the jewelry store, and Mr. Orange's shooting a woman who shot him in the stomach as he and Mr. White attempted to steal her car.

The remainder of the heist group returns to the warehouse to find Mr. Blonde dead. Mr. Orange claims that Mr. Blonde was going to kill Nash, Mr. Orange and the rest of the gang so that he could take the diamonds for himself. Eddie does not believe the story and, furious with Mr. Orange, fatally shoots Nash three times. Joe Cabot himself arrives and, after informing the group that Mr. Blue was killed, confidently accuses Mr. Orange of being an informant, forcing Mr. White to defend his friend. A shootout ensues, leaving Joe and Eddie dead, Mr. White severely wounded, and Mr. Orange mortally wounded. Mr. Pink, who avoided the shootout, takes the cache of diamonds and flees the warehouse. As police sirens and gunshots are heard outside, Mr. White cradles Mr. Orange in his arms and Mr. Orange reveals that he is in fact a detective. Mr. White kills Mr. Orange as the police raid the warehouse, resulting in the police killing Mr. White.