In Chicago, 1924, naïve Roxie Hart visits a nightclub where star Velma Kelly performs ("All That Jazz"). Roxie begins an affair with Fred Casely, whom she believes will make her a vaudeville star. After the show, Velma is arrested for killing her husband and sister after finding them in bed together. A month passes and Casely, when Roxie becomes too clingy for his taste, admits that he lied about his connections so she would sleep with him. Enraged, Roxie fatally shoots him with a gun and convinces her husband Amos to take the blame, telling him she has killed a burglar and that he is likely to be released on self-defense. As he confesses to the detective, Roxie fantasizes that she is singing a song devoted to her husband ("Funny Honey"). However, when the detective brings up evidence that Roxie knew Casely and they were having an affair, Amos comes clean and Roxie furiously admits what happened and is sent to Cook County Jail. Ambitious District Attorney Harrison informs the press he intends to seek the death penalty.
Upon her arrival Roxie is sent to Murderess' Row, under the care of the corrupt Matron "Mama" Morton, ("When You're Good to Mama"). Roxie meets Velma and learns the backstories of the other women in Murderess' Row ("Cell Block Tango"). She attempts to befriend Velma, whom she idolizes, but is rudely rebuffed. On Morton's advice, Roxie decides to engage Velma's lawyer, the brilliant Billy Flynn ("All I Care About"). Flynn and Roxie manipulate the press at a press conference, reinventing Roxie's identity as an originally virtuous woman turned bad by the fast life of the city; she claims to have had an affair with Casely because Amos was always working, but wanted to reform herself and start a family with Amos, which made Casely jealous. The press believe the story and turn her into a tragic heroine praised by the public ("We Both Reached for the Gun"). Roxie becomes an overnight sensation ("Roxie"), which infuriates Velma as it takes away the attention from herself. Velma tries to convince Roxie to doing a double-act, replacing the sister that she murdered ("I Can't Do It Alone"), but Roxie, now the more popular one of the two, snubs her like Velma originally did and the two begin a rivalry.
Roxie's fame dwindles when Kitty Baxter, a wealthy heiress, is arrested for the murder of her husband and his two lovers, and the press and Flynn pay more attention to Kitty. Roxie, to Velma's surprise, quickly steals back the fame when she pretends to be pregnant. However, Amos is ignored by the press ("Mister Cellophane"), and Flynn, to create more sympathy for Roxie, convinces Amos that the child is not his and that he should divorce Roxie in the middle of her predicament. Roxie's fame makes her arrogant and over-confident and refuses Flynn's command to wear a very modest dress for her trial, and fires him when she believes she can win on her own. However, when she sees one of the women in Murderess' Row hanged, a Hungarian heavily implied to be innocent, she realizes the gravity of the situation and re-hires Flynn.
Roxie's trial begins and Billy turns it into a media spectacle ("Razzle Dazzle") with the help of the sensationalist reports of newspaper reporter and radio personality, Mary Sunshine. Billy discredits witnesses, manipulates evidence, and even stages a reunion between Amos and Roxie when she admits that the child is his, and they publicly reconcile. The trial seems to be going in Roxie's way until Velma appears with Roxie's diary, where she reads incriminating diary entries in exchange for amnesty. Billy discredits the diary, implying that the prosecuting attorney was the one who planted the evidence ("A Tap Dance"). Roxie is acquitted, but her fame dies a few seconds later when a woman shoots her husband just outside the court. Flynn tells her to accept it, and admits that he tampered with her diary and gave it to Mama, who gave it to Velma, in order to both incriminate the district attorney and free two clients at once. Amos remains loyal and excited to be a father, and she cruelly rejects him and reveals her fake pregnancy, and he finally leaves her.
Roxie eventually becomes a vaudeville actress, but is very unsuccessful ("Nowadays"). Velma approaches her, implied to be just as unsuccessful, and suggests that a pair of murderesses in vaudeville would become a famous act. Roxie refuses at first, but accepts when they realize that they can perform together despite their resentment for each other. The two stage a spectacular performance that earns them the love of the audience and the press ("Nowadays / Hot Honey Rag"). The film concludes with Roxie and Velma receiving a standing ovation from an enthusiastic audience, and, as flashbulbs pop, proclaiming that "We couldn't have done it without you".