Volpone, wealthy and childless, is a con artist who attracts legacy hunters by pretending to be on the verge of death. Volpone's "clients" - including Corvino, Corbaccio, Voltore, and Lady Would-be Politic - bring him presents in the hopes of being included in his will. At the opening of the play, Volpone delivers a soliloquy in which he literally worships his gold while his servant Mosca, often called his Parasite, flits around and periodically interrupts him with flattery. Nano, Castrone, and Androgyno - Volpone's buffoons - enter and perform a skit which gives a sarcastic account of the transmigration of Pythagoras's soul. The entrance of Voltore, a lawyer, dispatches the buffoons. Voltore brings an antique plate and is told he will be Volpone's sole heir. Corbaccio and Corvino enter in succession, bringing a bag of gold coins and a pearl, respectively, and are also told that they will be heir to Volpone's fortune. Mosca is responsible for their deception, including Corbaccio's false belief that disinheriting his son Bonario will eventually pay dividends. Lady Would-be also comes to the door but is told to return later. Mosca describes the beauty of Corvino's wife Celia to Volpone, who decides he must see her for himself. They agree to go to her house in disguise.
Fellow Englishmen Sir Politic Would-be and Peregrine are seen in the public square outside Corvino's house at the opening of Act Two. They discuss a series of rumors involving animals which Sir Politic interprets as bad omens for the English state. Mosca and Nano interrupt their discussion as they enter to set up a stage. Volpone, disguised as a mountebank, takes the stage and delivers a sales pitch for an elixir. When he asks for a handkerchief from the audience, Celia throws hers down to him. Corvino enters and furiously disperses the crowd.
Back at his house, Volpone swoons for Celia. He gives Mosca permission to use his fortune in whatever way is necessary to woo Celia. At Corvino's house, Corvino sharply reprimands Celia for showing favor to a mountebank. He brandishes his sword and threatens her with physical violence before Mosca knocks on the door. Mosca tells Corvino that Volpone is on the mend but is in need of a female companion to maintain his health. After due consideration, Corvino offers Celia and goes to tell her to prepare for a feast at Volpone's house.
Act Three begins in the street with a soliloquy from Mosca regarding the supposed superiority of natural-born parasites compared to learned parasites. Bonario enters and scorns Mosca, who breaks down crying. Mosca then tells Bonario that Corbaccio plans to disinherit Bonario. Mosca offers to bring Bonario hear it for himself. Back at Volpone's house, the entertainment provided by Nano, Castrone, and Androgyno is interrupted by the entrance of Lady Would-be, who talks Volpone's ear off and brings him a cap she made herself. Mosca enters and dispatches with her by telling her he saw her husband Sir Politic on a gondola with another woman. Mosca hides Bonario so that he may witness the conversation with Corbaccio. However, Corvino and Celia arrive early and Mosca is forced to move Bonario to the gallery. After considerable deliberation, Celia is forced to be alone with Volpone, who reveals to her that he is not actually sick. Volpone offers her his fortune, but she declines. Just as he begins to force himself on her, Bonario leaps out and rescues Celia, exiting through the window. Mosca, who has been wounded by Bonario, enters and attends to Volpone. Mosca then convinces Corbaccio and Voltore to go after Bonario.
At the opening of Act Four, Sir Politic and Peregrine discuss the ways of a gentleman. Sir Politic details his get-rich-quick schemes, one of which involves selling the Venetian state to the Turks. Lady Would-be enters and accuses Peregrine of being a woman who is seducing her husband. Mosca enters and convinces Lady Would-be that her husband's seducer is actually Celia. Though Lady Would-be apologizes to him, Peregrine vows revenge on Sir Politic for his humiliation.
At the Scrutineo, Voltore, Corbaccio, Corvino, and Mosca get their story straight. Though they side with Bonario and Celia at the opening of the case, the Avocatori eventually align themselves with Voltore, who argues that Bonario committed adultery with Celia and attempted to kill his father. Lady Would-be testifies that Celia seduced her husband. Bonario and Celia have no witnesses of their own, so they lose the case.
Volpone's soliloquy at the beginning of Act Five foreshadows his punishment at the end of Act Five. He complains that, during the court case, he began to feel the pains which he has been faking for so long. He downs a glass of wine to "shake it off" (5.1.8) and Mosca enters to celebrate their unsurpassable masterpiece. Mosca goads Volpone to begin cozening his "clients," so Volpone writes a will naming Mosca as heir and spreads the word that he is dead. When Volpone's "clients" enter and discover that they have been duped, Mosca berates them one by one as Volpone looks on from behind the curtain. Volpone and Mosca decide to disguise themselves and continue tormenting the "clients" in the street.
At Sir Politic's house, Peregrine plays a practical joke on Sir Politic. Pretending to be a messenger, Peregrine tells Sir Politic that he has been reported for his plan to sell Venice to the Turks. Sir Politic panics, instructs his servants to burn his notes, and hides under a large tortoise shell just as three merchants, dressed as statesman, enter the house. Once the merchants discover Sir Politic under the shell, Peregrine tells him they are even and leaves. Sir Politic decides to leave Venice forever since his reputation has been so damaged.
In the street, Volpone, disguised as a commendatore, torments Corbaccio, Corvino, and Voltore by pretending he has heard news that they inherited a fortune. Voltore cracks and goes to the Scrutineo to confess that he lied during the previous court case. He gives his notes to the Avocatori but when Volpone, still disguised, tells him that Volpone is still alive, Voltore retracts his confession and pretends he was possessed while making it. While debating over whether to turn himself in, Volpone discovers that Mosca has locked him out of his own house. After being summoned by the Avocatori, Mosca arrives at the Scrutineo and affirms that Volpone is dead. Volpone beseeches him to say that Volpone is still alive, but Mosca demands half of his fortune. When Mosca and Volpone cannot agree to share the fortune, Volpone is apprehended by officers of the court. Before he is led away, however, Volpone unmasks himself and brings Mosca down with him. The Avocatori then hand down punishments to Volpone, Mosca, and the rest of the "clients." To conclude the play, Volpone speaks to the audience and asks for applause.