Los Angeles bank teller Francesca "Frankie" Sutton witnesses a robbery in the bank where she works. As a result, four people are killed, and Frankie is fired due to her recognizing one of the robbers from her Southern California neighborhood. During the investigation Detective Strode falsely implicates her as an inside accomplice. Frankie is forced to take a menial job at Luther's Janitorial Services with her three best friends, Lida "Stony" Newsom, Cleopatra "Cleo" Sims, and Tisean "T.T." Williams. The owner, Luther, treats them with disrespect and pays them paltry wages.
Stony's brother, Stevie, has been accepted into UCLA. Wanting to pay for his tuition, Stony begs her boss, used car salesman Nate, for an advance. Nate agrees to the advance on one condition: that Stony have sex with him, to which she reluctantly agrees. Stevie then admits to a livid Stony that he lied about getting into UCLA.
Tired of being mistreated, Frankie plans to commit a bank robbery with her friends. Cleo agrees, but Stony and T.T. are reluctant. Stevie is then gunned down by the police after being mistakenly identified as one of the robbers. Meanwhile, T.T.'s son is taken away from her by Child Protective Services, after he is accidentally poisoned at her workplace (T.T. had brought him with her, because she couldn't afford a babysitter). In view of all this, T.T. and Stony agree to join the robbery.
While casing a bank with T.T., Stony hits it off with Keith Weston who is the bank's manager. He and Stony begin dating. The four women embark on a series of successful bank robberies due to Frankie's inside knowledge of bank protocol with money and security. An investigation by the LAPD ensues. Detective Strode suspects that Cleo (because of her prior convictions), Frankie (because of her inadvertent connection to the earlier robbery and subsequent firing) and Stony (because of her brother's death) are involved. Yet he is unable to bring any of them in, since Frankie's careful planning has left him without sufficient evidence.
Concerned with the safety of their money, the four women stash the loot in an air vent at one of their work sites. When Cleo, Frankie, and T.T. arrive to work and discover they have a new boss, they realize that Luther has discovered the loot and fled with it.
Stony attends a banking event with Keith, and they end the night with sex. With the help of Blacc Sam, an arms dealer, the other three women track Luther to a motel, and find him sleeping with a prostitute. When the threesome demand that he return their stolen money, Luther instead threatens them with a gun; T.T. shoots him dead. Cleo steals the prostitute's driver's license as insurance and flees the hotel room with T.T. and Frankie. Cleo is brought in by Detective Strode for questioning about Luther's murder, but she intimidates the prostitute into not identifying her. When Stony discovers what has happened, she becomes disillusioned with her three partners. The foursome agree to skip town after pulling one more heist.
The women plan to rob the Downtown Federal Bank: the city’s largest, where Keith works. Concerned for Keith's safety, and not wanting him to know she's a bank robber, Stony asks him to meet her at a café on the far side of town. The four women pull off the robbery, stealing more money than they planned to.
Detective Strode and his partner arrive on the scene and order the robbers to surrender. Just as T.T. is about to do so, a bank security guard shoots and mortally wounds her. The guard, in turn, is gunned down by Stony. Enraged, Cleo opens fire to cover their escape. As they flee, T.T. dies in Stony's arms. The three surviving robbers, unable to outrun the police, split up. Cleo tells Stony and Frankie to keep her and T.T.'s shares of the stolen money.
Cleo leads the police on a high-speed chase until she is cornered, then wrecks her car by crashing through a police barricade. Refusing to surrender, she engages in a shootout with police and is gunned down, much to the dismay of her girlfriend Ursula, who has been watching the entire chase on TV.
Meanwhile, Detective Strode locates Frankie and demands that she surrender. Instead she sticks a gun in Strode's face, and reminds him of how he was a catalyst for this situation in the first place. Turning away from Strode, she is shot and killed from behind by his men.
Stony, who has successfully blended in with a tourist group heading to Mexico, tearfully watches Frankie's death from a passing charter bus. Detective Strode sees her from a distance but, out of guilt for his prior actions, lets her leave.
In Mexico, Stony cuts off her hair. She mourns the deaths of her brother and three friends. Then she calls Keith, both to assure him that she's all right and to thank him. He smiles. Stony drives off with half of the money from her and her friends' bank spree.
The film concludes with a climactic robbery and the fates of the four women sealed as the police close in.
Set It Off’s ending underscores the ultimate cost of the characters’ choices, shaped by societal pressures and personal loss. The conclusion drives home the personal and systemic tragedies at play, with each woman’s arc culminating in a blend of fleeting agency and hard consequences. The film closes on a sobering note about the limitations placed on those who dare to fight back against a stacked system.