The play's complexity, sophistication, and satire made it a poor fit with the repertory of Queen Anne's Men at the Red Bull Theatre, where it was first performed.

The story is loosely based on an event in Italy thirty years prior to the play's composition: the murder of Vittoria Accoramboni in Padua on 22 December 1585.

The Duke of Brachiano has conceived a violent passion for Vittoria Corombona, daughter of a noble but impoverished Venetian family, despite the fact they are both married to other people.

Vittoria's brother Flamineo, employed as a secretary to Brachiano, has been scheming to bring his sister and the Duke together in the hope of advancing his career, much to the dismay of their mother, Cornelia.

Next, Zanche, Vittoria's Moorish maid, who has fallen in love with her supposed countryman Mulinassar, reveals to him the murders of Isabella and Camillo and Flamineo's part in them.

Flamineo is banished from court for the murder of his brother Marcello by Brachiano's son Giovanni, the new Duke, and sensing that his crimes are catching up with him he goes to see Vittoria.

In the prefatory epistle to the quarto, Webster praised the actors, mentioning Richard Perkins; but complained of the winter weather and above all of the audience, whose intellect he compared to that of donkeys.

The first successful modern production was that of the Marlowe Society (ADC Theatre, Cambridge, March 1920), with music by C. Armstrong Gibbs and with Eric Maschwitz as Vittoria.

The Society specialised in Elizabethan and Jacobean revivals in uncut texts performed with their original economy and rapidity, and with the female roles played by men.

"[7] A London production in 1947 at the Duchess Theatre directed by Michael Benthall featured Hugh Griffith as Monticelso, Patrick Macnee as Hortensio/Spanish Ambassador, Claire Bloom as one of the Ladies of Brachiano's court, Margaret Rawlings as Vittoria and Andrew Cruickshank as the Duke of Florence.

In 1965, an Off-Broadway production was staged at the Circle in the Square starring Frank Langella as Flamineo, Carrie Nye as Vittoria, Paul Stevens as Brachiano, Robert Burr as Francisco, Eric Berry as Monticelso and Christina Pickles as Cornelia.

The Royal Shakespeare Company performed The White Devil in 1996 at the Swan Theatre in Stratford-upon-Avon (later transferred to London to The Pit at The Barbican), directed by Gale Edwards with Richard McCabe as Flamineo, Philip Quast as Ludovico, Ray Fearon as Brachiano, Jane Gurnett as Vittoria, Stephen Boxer as Francisco and Philip Voss.

The company returned to the play in 2014 with a production in the Swan Theatre in Stratford-upon-Avon, directed by Maria Aberg with David Sturzaker as Bracciano, Kirsty Bushell as Vittoria, David Rintoul as Cardinal Monticelso, Simon Scardifield as Francisco and Joseph Arkley as Ludovico; in this production, Flamineo, Vittoria's brother, was played by a woman (Laura Elphinstone).

The production featured Patrick Kennedy as Flamineo, Anna Maxwell Martin as Vittoria, Frances de la Tour as Cornelia, Shaun Dingwall as Brachiano, Peter Wright as Francisco, Sean Baker as Monticelso and Harry Myers as Ludovico.

On 26 January 2017 a run started at the Sam Wanamaker Playhouse, London (a venue embodying the features of a typical theatre from the period of the original seventeenth century production).