A young, beautiful nobleman, Calisto, stumbles upon a young noble girl’s garden while searching for his lost falcon and falls madly in love. When Calisto compliments the girl, Melibea, on her beauty, she reproaches him, sending him away for insulting her honor. Calisto returns home, dejected. He lashes out at his servant, Sempronio, who is disgusted with his master’s overly dramatic response to romantic rejection. Sempronio tries to cheer Calisto up by telling him that all women are evil and lead men astray. The more he insults women, however, the greater Calisto’s desire for Melibea grows. Sempronio, recognizing an opportunity to manipulate and take advantage of Calisto, says he knows someone who can help him win over Melibea—an old madam named Celestina who practices witchcraft.

Sempronio heads to Celestina’s house, where his lover, Elicia, one of Celestina’s prostitutes, also lives. He invites Celestina for a walk, flattering her by saying that he never forgets to include her when he comes across an opportunity to make money. Sempronio explains Calisto’s situation, and Celestina instantly recognizes that Calisto is an easy target. They agree to work together to manipulate Calisto and split the rewards for helping Calisto win over Melibea. Celestina advises they draw out the situation for as long as possible to make Calisto more hopeless and desperate so he’ll give them even more money.

The pair return to Calisto’s house, where Calisto and his other servant, Pármeno, are waiting inside. Pármeno, recognizing Celestina from his past as her servant, tells Calisto that Celestina deals in many trades, which are all a front to her real trade, which is prostituting women and repairing “maidenheads” to make women appear to be virgins again. Calisto tells her about his desperate situation, while Pármeno makes nasty comments about Celestina on the side, within Celestina’s earshot. Celestina agrees to help Calisto, who gives her an advance in gold. Before she leaves, she takes Pármeno aside, advising him that no real friendship can occur between people of unequal status and that he should be loyal to her and Sempronio. Celestina then promises Pármeno Areúsa, Elicia’s cousin, to seal his favor. Pármeno is swayed by Celestina but struggles with his conscience.

Celestina returns home to craft her plan. She casts a spell on a spool of thread to conjure the devil’s help. She finds Melibea with her servant Lucrecia. Celestina tells Melibea she’s on an errand for Calisto, who has a toothache and would like her girdle, which is known to have touched holy relics. Melibea is angry at Celestina at first, condemning her for trying to manipulate her, but is soothed when Celestina speaks. Lucrecia, highly suspicious of Celestina, tries to interfere to protect Melibea, but Celestina quiets her by promising her cosmetics to help her win a husband. Melibea tells Celestina to come back later for a prayer for Calisto.

Celestina rushes to Calisto’s house to tell him the good news. She sees Sempronio on the way, who becomes suspicious that Celestina has changed course. Celestina shows Calisto the girdle and asks him for a new cloak in exchange. Calisto, ecstatic over her success, hastily orders Pármeno, who has been condemning Celestina the whole time, to send for a tailor right away. Celestina takes Pármeno aside to persuade him to stop interfering. She reminisces about her younger days with Claudina, Pármeno’s mother, whom she credits with teaching her everything about witchcraft and defying authority. Pármeno asks whether her promise still stands to get him Areúsa. Celestina brings him to Areúsa’s house, where she convinces a reluctant Areúsa to sleep with Pármeno, who is now on her side.

Melibea calls for Celestina to come to her house, saying her heart hurts. Celestina guesses that her spell has worked and Melibea has fallen for Calisto. Melibea tells Celestina Calisto can see her at midnight. Celestina rushes to tell Calisto, who is in a church praying. Overcome with joy, he offers a gold chain as a reward on the spot. Pármeno is skeptical that Celestina will ever share any profits from the chain, which will be hard to divide up, but Sempronio assures him they’ll get their reward out of Celestina, one way or another.

Calisto, Sempronio, and Pármeno arrive at Melibea’s house at midnight. Calisto climbs a ladder to enter Melibea’s room. While Sempronio and Pármeno wait for Calisto outside, they hear noises and argue if they should run. Meanwhile, Melibea begs Calisto to wait for sex to protect her reputation and to be satisfied that she loves him. She tells him to return the next night. Outside, Sempronio and Pármeno finally decide to run away, scared they’re being discovered. Calisto hears them, believing they’re chasing someone away for him.

Sempronio and Pármeno head to Celestina’s house to claim their part of the chain. When Celestina tells them the chain is lost, Pármeno threatens her. Celestina calls for Elicia to summon the constable, saying her life is in danger. Sempronio, outraged, stabs Celestina. The men try to escape through the window, but the constable is outside already, waiting for them. Calisto awakens the next day to learn from his new servant, Tristán, and the stable boy, Sosia, that Sempronio and Pármeno have been executed in the town square and that they killed Celestina because she wouldn’t share the chain. Calisto laments their deaths but is more concerned about his reputation.

Calisto, Sosia, and Tristán go to Melibea’s house. Melibea tries to stop Calisto from overcoming her but fails, and they have sex. When Calisto leaves, Melibea fetches Lucrecia to ask if she heard them. Suddenly, Lucrecia hears noises outside, so they rush to see what happened. They discover Tristán, crying over Calisto, who has fallen to his death from the ladder. Overcome with grief, Melibea later confesses everything and kills herself by jumping from a tower while her father, Pleberio, watches below. Pleberio, bitter and distraught, muses on the destructive power of love and the meaninglessness of wealth without an heir to inherit it.