As with Sin City 1, there are three plot threads.
Plot 1: Dwight McCarthy is seduced by Ava Lord, who tells him that her husband is abusive and is using Manute to keep tabs on her at all times. Dwight tries to break into Ava's house to find out what's wrong, but is caught by Manute who beats him up and throws him out of the house. Dwight meets up with Marv and they return to the house, where Dwight kills Ava's husband and Marv rips out Manute's eye. Ava then reveals that her husband was innocent and she and Manute set this up so that Ava could seize her husband's inheritance. Ava shoots Dwight but doesn't kill him, just seriously damaging his face, and he and Marv escape.
Ava then tries to send the police after Dwight for her husband's murder, including seducing the lead detective on the case. Dwight returns to Old Town, where the armed prostitutes drive away the police and try to deal with his injuries, and he phones Ava to threaten vengeance. It's also revealed that Dwight saved Miho by shooting two men in a fight when she was 15 years old. The lead detective, in love with Ava, is warned off her by his partner and eventually kills him in a rage, then kills himself in regret. Ava tries to cosy up to a Mafia boss to send a "specialist" after Dwight; but the specialist turns out to _be_ Dwight, after he has had facial surgery which changes his appearance. The "specialist" Dwight is picked up by Gail as part of his plan and he, Gail, and Miho kill everyone on Ava's estate. Ava tries to seduce Dwight again, claiming that he is now more like her and they can be together, but he isn't fooled and shoots her.
Plot 2: Johnny Roarke, Senator Roarke's disowned son, arrives in Sin City and gambles at Katie's place, winning big on the slots, meeting up with a girl, and finally beating Roarke at poker in a backroom game. Roarke warns Johnny that he will pay for humiliating him in the game; and later that night he and his goons pick up Johnny, break the fingers of his right hand (which he held cards in) and shoot him in the leg. Johnny tries to contact the girl again and finds that Roarke has had her dismembered and beheaded for her role in the game. Johnny goes to a drunk old sawbones and trades the last of his money and his shoes for having his injuries patched up, picks up a single dollar from a waitress at a diner, wins at the slots again, and then goes straight back to the next poker game with Roarke. He reveals that he is ambidextrous and can play with either hand, and beats Roarke again. As he gloats that he has beaten Roarke twice in front of his influential friends in spite of Roarke's attempts to destroy him, Roarke shoots him in the head.
Plot 3: Katie is haunted by memories of Hartigan and believes that she must kill Roarke to avenge him. Her personality becomes increasingly deranged and her dancing more and more violent. Finally, she cuts off her hair and then slashes cuts in her own face with a glass shard, then tells Marv (who protects her) that Roarke is responsible for the slashing. She and Marv rush through Roarke's estate killing everyone with shotguns and a crossbow, then Marv is wounded by a misfiring shotgun, leaving Katie to face Roarke alone. Katie accidentally shoots Roarke's reflection in a mirror, allowing Roarke to shoot her; then, as Roarke is gloating, a stroke of lightning shows Hartigan's reflection in the mirror, which distracts him allowing Katie to grab her gun and shoot Roarke in the shoulder. She then steps up and shoots Roarke in the head and the film ends immediately after the shot is fired.