The plan involves setting Morose up to marry Epicoene, a boy disguised as a woman (though none of the other characters know this until the final scene of the play).
Morose soon regrets his wedding day, as his house is invaded by a charivari consisting of Dauphine, Truewit, and Clerimont; a sea-captain named Otter and his wife; two stupid knights (La Foole and Daw); and an assortment of Collegiates.
Desperate for a divorce, Morose consults two lawyers (who are actually Dauphine's friends Cutbeard and Otter in disguise), but they can find no grounds for ending the match.
The agreement made, Dauphine strips the female costume from Epicœne, revealing that Morose's wife is, in fact, a boy, and therefore their marriage cannot be upheld.
Morose is dismissed harshly, and the other ludicrous characters are discomfited by this revelation; Daw and Foole, for instance, had claimed to have slept with Epicœne.
While most details of characterisation and plot are his own invention, the scenario originates from two orations by Libanius: in one, a groom in Morose's situation argues for permission to commit suicide to escape his marriage, while in the other an elderly miser plans to disinherit a nephew who laughed at him.
The coup de théâtre of Epicœne's unveiling, while traditionally viewed as derived from the Casina of Plautus, is closer both in spirit and in execution to Il Marescalco of Aretino.
Finally, the comic duel between La Foole and Daw is usually seen as an echo of the mock-duel between Viola and Aguecheek in Shakespeare's Twelfth Night.
This can be seen through the play's use of Latin phrases, which would have required the audience to possess advanced education in order to understand all of the jokes and references.
Jonson hinted to William Drummond that the play failed; he mentioned certain verses calling the title appropriate, since the audience had remained silent at the end.
After the Restoration, Epicœne was frequently revived and highly appreciated; in the course of a lengthy analysis, Dryden calls it "the pattern of a perfect play."
The revamped casting did not save the production, and Epicœne vanished from the boards for over a century, a victim of the falling popularity of non-Shakespearean Renaissance dramas.
In 1935, Richard Strauss's opera Die schweigsame Frau, with a libretto by Stefan Zweig based on Jonson's play, premiered in Dresden.
The play was adapted for radio by the BBC and featured Marius Goring, Laidman Browne, Gabriel Wolf, Norman Shelley, Vivienne Chatterton, June Tobin, and David Spenser.