Volpone, a Venetian nobleman, has no relative to make his heir; he must name someone his beneficiary. Several rivals try to attain his favor by bringing the sick Volpone gifts that they hope will be returned tenfold. Mosca, a clever parasite to Volpone, encourages the three major gulls to give until it hurts. These birds of prey are Voltore, a lawyer; Corbaccio, an old miser about to die himself; and Corvino, a rich merchant and husband to Celia, a beautiful lady of Venice. Also naively competing for Volpone's wealth is Lady Would-be, the affected wife of an English knight, Sir Politic Would-be. After each gull is fleeced before our eyes, Mosca encourages Volpone to think of seeking a greater treasure than gold: the wife of Corvino. After a sensuous description by Mosca, Volpone resolves to see this paragon of beauty.
As the second act begins, Volpone appears beneath Celia's window disguised as a mountebank. Jealous Corvino drives him away upon discovering his wife in an upper window. While Corvino threatens his wife with closer incarceration, Volpone sings to Mosca of her beauty and his desire. Mosca hatches a plot to secure Celia for his master. He tells Corvino that the mountebank's oil, purchased for Volpone by Corbaccio, has revived the flagging health of the fox. However, if Volpone is to live on, he must sleep with some young woman. The others are seeking the cure for Volpone, and Corvino must hurry or lose his investment. Corvino wisely suggests a courtesan, but Mosca slyly rejects this plan, reasoning that an artful quean might cheat them all. Finally, Corvino offers his wife. He is convinced that she is safe, and Mosca is sent to tell Volpone the good news.
Act III reveals Mosca and Bonario conversing in the street. For some reason, Mosca is telling Bonario of Corbaccio's intention to disinherit him and inviting the son to witness the deed at Volpone's house. Meanwhile, Lady Would-be visits Volpone and nearly talks him to death. Mosca gets rid of her by saying that Sir Politic was lately seen rowing in a gondola with a cunning courtesan. Corvino arrives, dragging his unwilling wife into the fox's lair; Volpone, left alone with the shrinking lady, is not successful in his persuasive attempts to seduce her. Just as he is about to take her by force, Bonario leaps from his hiding place and denounces Volpone and spirits the lady to safety.
Mosca saves Volpone from the police by explaining the incident to the three gulls and persuading them to tell his contrived story in court. Mosca says that Bonario, impatient to see Volpone, discovered the fox with Celia, seized the lady, and made her swear that Volpone had attempted to rape her. The plan is to get an injunction against Bonario.
Act IV begins with the subplot of Sir Politic Would-be and Peregrine. Sir Politic is discovered entertaining his fellow Englishman with his naive understanding of politics. Lady Would-be interrupts the conversation and mistakes Peregrine for the courtesan. She apologizes upon discovering her mistake, but Peregrine leaves in a huff and promises to take his revenge for the affront.
At the court, Voltore succeeds in making Celia and Bonario look like lovers. Mosca persuades Lady Would-be to testify that Celia was the bawd in the gondola with her husband. Volpone makes his entrance on a stretcher to demonstrate his impotence.
All augurs well for the rogues as the fifth act begins. But Volpone cannot leave well enough alone. He sends his servants to announce his demise and waits for the gulls to come to claim their inheritance. Mosca is the heir! The parasite flaunts his knowledge of their wrongdoing to the birds of prey and they leave in despair. Disguised as a police officer, Volpone follows them to taunt them further.
Meanwhile, Peregrine, disguised as a merchant, comes to Sir Politic's house and tells the knight that the police are seeking him because he has plotted to overthrow the Venetian state. When Sir Politic hides in a tortoise shell, Peregrine calls in some other merchants to mock and humiliate the foolish Englishman.
At the court, the three gulls, enraged by Mosca and Volpone and the loss of their hopes, decide to tell the truth. They accuse Mosca of being the lying villain who created the whole plot. Mosca is summoned and arrives with another plot in mind. He will extricate Volpone from this predicament, but the fox must remain dead and he, Mosca, must continue as the heir. Volpone throws off his disguise and the entire intrigue is revealed.
The court sentences Mosca to the galleys; Volpone is deprived of his goods and sent to a hospital for incurables. The gulls are deprived of a legal practice, a wife, and a fortune. Celia returns to her father with her dowry trebled, and Bonario is his father's heir immediately.