This fifteenth-century Spanish tale tells of the doomed romance between Calisto and Melibea. Calisto lusts after Melibea when he chances upon her in her garden. For her part, Melibea is deeply suspicious of Calisto's intentions and will have nothing to do with him, and Calisto has little choice but to return home. There, a trusted servant named Sempronio advises him to seek the services of Celestina, a brothel owner. Sempronio is deeply in love with Elicia, one of Celestina's servant girls.

In a betrayal of his employer, Sempronio decides to work with Celestina to get as much gold as possible from Calisto. Meanwhile, Parmeno (another of Calisto's servants) warns Calisto against trusting the evil and untrustworthy Celestina. He advises Calisto to seek Melibea's hand honorably rather than to rely on the notorious madam. The lovesick Calisto refuses to listen and seeks out Celestina anyway. Knowing that Parmeno is against her, Celestina decides to bribe him. She tells him that he can have Areusa (another of her servants), and since Parmeno is already in love with Areusa, he gives in to Celestina. Now, Sempronio and Parmeno are both working with Celestina to cheat their master out of as much gold as they can.

Celestina makes her way to Melibea's home as a vendor of feminine products. She worms her way into the confidence of Melibea's mother, Alisa. Eventually, Alisa leaves Celestina alone with Melibea. The madam immediately engages in a series of manipulations to wear Melibea down. Celestina tells Melibea that Calisto is sick and must have her sacred girdle and a copy of Saint Polonia's prayer in order to heal. Bewildered by what she is hearing, Melibea agrees. Celestina returns the next day to pick up the items, and Melibea agrees to meet with Calisto. The two begin a love affair. Meanwhile, Sempronio and Parmeno engage in sexual liaisons with Elicia and Areusa respectively. After Calisto begins to bed Melibea regularly, both Sempronio and Parmeno decide it's time to get their agreed-upon portion of gold from Celestina, but she refuses to hand over the men's share of Calisto's gold.

The men kill Celestina in anger, but Elicia witnesses their treachery. The authorities catch Sempronio and Parmeno in the act of fleeing and they are beheaded. Both Elicia and Areusa decide to avenge their lovers' deaths. They team up with Sosia (another of Calisto's servants) and Centurio (a ne'er-do-well) to create a distraction while Calisto is engaged in one of his romantic trysts with Melibea.

Centurio's friends and Sosia make such a racket that Calisto's attention is drawn to the noise. He climbs a ladder to determine the source of the commotion outside Melibea's home; in doing so, Calisto loses his balance and falls to his death. After realizing that her lover is dead, Melibea confesses her affair to her parents and leaps to her death from the roof of her home.