As the book opens, Fauchery, a drama critic, is waiting for the hottest play in Paris to open. "The Blonde Venus" has bad music and bad actresses, but a new star, Nana, who appears on stage clad only in a diaphanous wrap brings down the house anyway. Nana is an experienced concubine. She exploits the hysteria caused by her nearly nude performance to win Steiner, a wealthy banker. Steiner buys her a country house where she entertains other lovers to win more gifts. Here she also has a brief affair with the penniless student George.

Steiner soon sets her loose and she takes up with Fontan, an actor. She tries to be domestic and kind, but Fontan beats her, then abandons her and she turns to streetwalking. Threatened by the police, who in order to prevent the spread of syphilis can imprison women and perform mandatory gynecological exams, she quickly searches for a new, wealthy lover. She finds Muffat whom she humiliates, trampling on his uniform and sleeping with whomever she likes. One day, Muffat finds her in the arms of young George and then with his elderly father-in-law. Nana also brings home Stain, a streetwalker, to be her lover and confidant.

Young George finally grows so jealous of Muffat and of his brother, another of Nana's conquests, he kills himself in her bedroom. Her other lovers must step over the bloodstain to approach Nana's bed. Soon after, Nana catches smallpox and dies miserably, the disease ravaging her beauty. She dies in 1870 just as the Franco-Prussian War begins.