The Salesman walks onto a penthouse balcony where The Customer looks out over Basin City. He offers her a cigarette and says that she looks like someone who is tired of running and that he will save her. The two share a kiss and he shoots her; she dies in his arms. He says he will never know what she was running from but that he will cash her check in the morning.
On the docks of Sin City, aging police officer John Hartigan tries to stop serial child-killer Roark Junior from raping and killing his fourth known victim, eleven-year-old Nancy Callahan. Junior is the son of Senator Roark, who has bribed the police to cover up his son’s crimes. Hartigan’s corrupt partner, Bob tries to convince Hartigan to walk away; Hartigan knocks him out.
Hartigan, experiencing pain from a bad heart, heads into the warehouse where Roark Junior and several henchmen are holding Nancy. Junior shoots Hartigan in the shoulder and tries to escape. Hartigan catches up and shoots off Junior’s ear, hand and genitals. Bob, now recovered, shoots Hartigan in the back. As the sirens approach, Bob leaves and Nancy lies down in Hartigan’s lap. Hartigan passes out, reasoning his death is a fair trade for the girl’s life.
After a one-night stand, Marv awakens to find Goldie has been killed while he slept. He flees the frame-up as the police arrive, vowing to avenge her death. His parole officer, Lucille, warns him to give up on this mission, believing Marv may have imagined it all due to his “condition”. Marv interrogates several informants, working up to a corrupt priest, who reveals that the Roark family was behind the murder. Marv kills the priest but is then attacked by a woman who looks like Goldie, which he dismisses as a hallucination.
Marv goes to the Roark family farm and is subdued by the silent stalker who killed Goldie. He awakens in the basement to find Lucille has been captured after looking into his story. She tells Marv that the killer is a cannibal and that Goldie was a prostitute. He learns that the killer’s name is Kevin and escapes. Lucille is shot by the leader of a squad of corrupt cops. Marv kills the cops except for their leader, whom he interrogates. He learns that Cardinal Patrick Henry Roark arranged for Goldie’s murder.
Marv goes to Old Town, Sin City’s prostitute-run red-light district, to learn more about Goldie and is captured by her twin sister, Wendy, the attacker Marv previously dismissed as a hallucination. Once he convinces Wendy that he is not the killer, the two return to the farm where Marv kills Kevin. He confronts Cardinal Roark, who confesses his part in the murders. Kevin was the cardinal’s ward; the two men ate the prostitutes to “consume their souls”. Marv kills the cardinal but is then shot and captured by his guards.
Marv is taken to a hospital where cops threaten to kill his mother, to get him to confess to killing Roark, Kevin and their victims. He is sentenced to death in the electric chair. Wendy visits him on death row and thanks him for avenging her sister. Marv is then executed.
Shellie is being harassed by her abusive ex-boyfriend Jackie Boy and his cronies. Her boyfriend, Dwight violently warns him to leave Shellie alone. Jackie Boy and his cronies flee to Old Town. Dwight follows and sees them harass Becky, a young prostitute. Gail, the prostitutes’ leader and Dwight’s on-and-off lover, also witnesses the scene. When Jackie Boy threatens Becky with a gun, Miho, a martial arts expert, kills Jackie Boy and his friends. They realize Jackie Boy is actually Detective Lieutenant Jack Rafferty of the Basin City Police, considered a “hero cop” by the press. If the cops learn how he died, their truce with the prostitutes would end and the mob would be free to wage war on Old Town.
Dwight takes the bodies to a tar pit, where he is attacked by an ex-IRA mercenary hired by mob boss Wallenquist. He nearly drowns in the tar before Miho saves him. The mercenary flees to the sewer with Jackie Boy’s severed head but Dwight and Miho retrieve it and return to Old Town. Meanwhile, mob enforcer Manute kidnaps Gail. Becky, threatened with the death of her mother by the mob, betrays the prostitutes. Manute prepares the mob’s invasion of Old Town. Dwight trades Jackie Boy’s head for Gail’s freedom but the head is stuffed with explosives; Dwight detonates it, destroying the evidence and Gail’s captors. The other prostitutes gun down the mercenaries while Becky, injured in the fight, escapes.
Hartigan is recovering in a hospital when Senator Roark informs him that Junior is in a coma and the Roark legacy is in serious jeopardy. Hartigan will be framed for Junior’s crimes; if he tells anyone the truth, they will die. A grateful Nancy promises to write letters every week while he is in prison. Hartigan goes to jail, though he refuses to confess. He receives a weekly letter from Nancy, as promised. After eight years, the letters stop and he receives a severed finger instead. Hartigan confesses to all charges, leading to his parole, and searches for an adult Nancy, not knowing he is being followed by a deformed, yellow man. He eventually finds her at Kadie’s Bar, where she has become an exotic dancer.
He realizes he was set up to lead the yellow man to Nancy and the two escape in Nancy’s car. Hiding in the trunk of Hartigan’s car, the deformed man returns, revealing himself as Roark Junior, disfigured by years of surgery to regenerate his body parts. Junior attacks Hartigan and takes Nancy to the Roark farm to finish what he started eight years before. Hartigan follows and fakes a heart attack, giving him a chance to kill Junior. Knowing that Senator Roark will never stop hunting them, Hartigan commits suicide to ensure Nancy’s safety. Again, he justifies his life for Nancy’s as a fair trade.
An injured Becky departs from a hospital, talking on a cell phone with her mother. In the elevator she encounters The Salesman, dressed as a doctor. He offers her a cigarette, calling her by name, and she abruptly ends the call with her mother.