Volpone is an old, wealthy man without children living in Venice, Italy. With Mosca, his parasite (which means a hanger-on, a low-born servant or follower living off a wealthier person), Volpone stages an elaborate scam. Volpone pretends to be deathly ill, and is leading several people on to believe that they will be named his heir. Chief among them are Voltore, a lawyer; Corbaccio, an even older, sicker man; and Corvino, a merchant. Mosca convinces each man that he is the front runner to be named heir, and each one showers Volpone with gifts and gold hoping to remain on his good side. After fooling each man, and even getting Corbaccio to disinherit his son, Volpone learns that Corvino has a beautiful wife (named Celia), and he decides to try to woo her.
Outside of Corvino’s home elsewhere in Venice, the English knight Sir Politic Would-be meets a fellow English traveler named Peregrine. Sir Politic is extremely gullible about news from home, and Peregrine asks him for travel advice because he thinks Sir Politic is so amusing.
Disguised as assistants to a mountebank (an Italian swindler), Mosca and Nano, Volpone’s dwarf, enter the square where Sir Politic and Peregrine have been talking. They are followed by a large crowd and by Volpone, who is dressed as a famous mountebank. In disguise, Volpone makes an elaborate sales pitch for a cure-all elixir. As planned, he attracts the attention of Celia, whose window is nearby. She throws down a handkerchief, but Corvino chases off the crowd and the mountebank before Volpone has a chance to speak with Celia.
Corvino is extremely controlling of Celia, and he makes violent threats to her for interacting with the mountebank. He plans to restrict her even more by forcing her to wear a chastity belt and forbidding her from even going near windows. Soon after making these threats, Mosca shows up at Corvino’s house, and he says that doctors have decided that the only cure for Volpone is to sleep with a young woman. By pitting him against Voltore and Corbaccio, Mosca is able to convince Corvino to offer Celia up to Volpone in exchange for being named heir.
While praising himself for his skills, Mosca meets Bonario, the son Corbaccio agreed to disinherit earlier in the play. Mosca brings Bonario to Volpone’s house and places him in a hiding spot so that he can witness his father disinheriting him, thereby creating more chaos and frustration for Volpone's victims. While Mosca is still gone, the extremely chatty Lady Would-be, Sir Politic’s wife, visits Volpone. Mosca arrives and gets rid of Lady Would-be by saying that he saw her husband with a prostitute. Mosca then hides Bonario to witness the staged will signing.
However, instead of Corbaccio arriving to disinherit Bonario, Corvino shows up early with Celia. When Corvino reveals to Celia why they are there, Celia resists, and after Corvino is unable to convince her to sleep with Volpone, who is still pretending to be diseased, Corvino leaves her alone with Volpone to see if she’ll be more willing in private. Volpone springs out of bed and tries to woo her. When that fails, he tries to rape her, but Bonario has been eavesdropping, and he jumps out to save her.
Mosca and Volpone prepare an elaborate lie to get out of trouble. Meanwhile, at the piazza, Sir Politc and Peregrine have an absurd discussion about potential business plans. They are interrupted, however, when Lady Would-be shows up, thinking that Peregrine is the prostitute Mosca saw with Sir Politic. She screams at Sir Politic and accuses Peregrine of being a whore dressed as a man, but Mosca soon arrives and says that the prostitute he saw is now in court before the Venetian senate. Peregrine believes that Sir Politic intentionally set him up to embarrass him. Later, in retaliation, Peregrine embarrasses Sir Politic by pretending that Sir Politic is wanted by the Venetian authorities.
In court, Voltore, Corvino, Corbaccio, and Mosca present a calculated lie framing Bonario and Celia. They say that Bonario wounded Mosca, tried to kill Corbaccio, and wants to defame Volpone by having Celia make a false rape accusation. All the while, Mosca continues to convince Voltore, Corvino, and Corbaccio that he is working for each of them exclusively. Volpone is forced to appear in court, and he convincingly acts diseased.
Though Mosca’s plan worked and Volpone is freed, Volpone is not satisfied. He decides to fake his death to further torture Voltore, Corbaccio, and Corvino. Volpone tells Mosca to tell the men that Mosca himself is the heir, and while hiding, Volpone watches Mosca infuriate Voltore, Corbaccio, Corvino, and Lady Would-be as they all find out that none of them have inherited the fortune. Volpone then disguises himself as an officer to further taunt everyone, but he pushes Voltore so far that Voltore decides to confess to the lie about Celia and Bonario that he told in court to claim Volpone’s innocence. Volpone is able to salvage the situation by claiming that Voltore was possessed when giving his confession, but then Mosca arrives in court.
Mosca, who has decided to swindle Volpone, has realized that, since Volpone is presumed dead with Mosca as his heir, Mosca can inherit the fortune by continuing to act like Volpone is dead. He uses this plan to secretly bargain for some of Volpone’s fortune in court, but the two cannot reach a deal. To prevent Mosca from getting away with all of his money, Volpone reveals himself and his entire plan. The Venetian court sentences Mosca to life in prison, they disbar and banish Voltore, they confine Corbaccio to a monastery and give all his money to Bonario, they publicly humiliate and legally divorce Corvino, and they provide the upper-class equivalent of a death sentence to Volpone.