The play was written for and performed by the King's Men in 1613 or 1614. The double cast lists included in the 1623 quarto suggest a revival around 1619. Contemporary reference also indicated that the play was performed in 1618, for in that year Orazio Busino, the chaplain to the Venetian ambassador to England, complained of the play's treatment of Catholics in the character of the Cardinal.
The quarto's cast list allows more precision about casting than is usually available. Richard Burbage and Joseph Taylor successively played Ferdinand to Henry Condell's Cardinal. John Lowin played Bosola; William Ostler was Antonio. Boy player Richard Sharpe played the title role not in the original 1612 production, presumably due to his age, but in the revival of 1619–23. Nicholas Tooley played Forobosco, and Robert Pallant doubled numerous minor roles, including Cariola.
The quarto title page announces that the play was performed at both the Globe Theatre and at Blackfriars; however, in tone and in some details of staging (particularly the use of special lighting effects) the play is clearly meant primarily for the indoor stage. Robert Johnson, a regular composer for Blackfriars, wrote incidental music for the play and composed a setting for the "madmen's song" in Act 4.
The play is known to have been performed for Charles I at the Cockpit-in-Court in 1630; there is little reason to doubt that it was performed intermittently throughout the period.
The play remained current through the first part of the Restoration. Samuel Pepys reports seeing the play several times; it was performed by the Duke of York's company under Thomas Betterton.
By the early eighteenth century, Webster's violence and sexual frankness had gone out of taste. In 1733, Lewis Theobald wrote and directed an adaptation, The Fatal Secret; the play imposed neoclassical unities on the play, for instance by eliminating the Duchess's child and preserving the Duchess at the end. By mid-century, the play had fallen, with Webster, out of the repertory, where it stayed until the Romantic revival of Charles Lamb and William Hazlitt. In 1850, after a generation of critical interest and theatrical neglect, the play was staged by Samuel Phelps at Sadler's Wells, with Isabella Glyn in the title role. The text was adapted by Richard Henry Horne. The production was favourably reviewed by The Athenaeum; George Henry Lewes, however, registered disapproval of the play's violence and what he termed its shoddy construction: "Instead of 'holding the mirror up to nature,' this drama holds the mirror up to Madame Tussauds." These would become the cornerstones of criticisms of Webster for the next century. Still, the play was popular enough for Glyn to revive her performance periodically for the next two decades.
Shortly after, Duchess came to the United States. Working with Horne's text, director James Stark staged a production in San Francisco; this version is noteworthy for a sentimental apotheosis Stark added, in which the Duchess and Ferdinand are reunited in heaven. The most popular American productions, however, were produced by Wilmarth Waller and his wife Emma.
William Poel staged the play at the Opera Comique in 1892, with Mary Rorke as the Duchess and Murray Carson as Bosola. Poel's playscript followed Webster's text closely apart from scene rearrangements; however, reaction had set in, and the production received generally scathing reviews. William Archer, England's chief proponent of Ibsen's new drama, took advantage of the occasion to lambast what he saw as the overestimation of Elizabethan theatre in general.
In 1919, the Phoenix Society revived the play in London for the first time in two decades. The production featured Cathleen Nesbitt as the Duchess; Robert Farquharson played Ferdinand. The production was widely disparaged. For many of the newspaper critics, the failure indicated that Webster had become a "curio"; T. S. Eliot, conversely, argued that the production had failed to uncover the elements that made Webster a great dramatist—specifically his poetry. A 1935 production at the Embassy Theatre received similarly negative reviews; Ivor Brown noted that the audience left "rather with superior smiles than with emotional surrender." In 1938, a production was broadcast on BBC television; it was no better received than the previous two stage productions.
In 1937, it was performed in Dublin, Ireland, at the Abbey Theatre, with incidental music composed by Arthur Duff.
In the aftermath of World War II, George Rylands directed a production at the Haymarket Theatre that at last caught the public mood. John Gielgud, as Ferdinand, accentuated the element of incestuous passion in that character's treatment of the Duchess (played by Peggy Ashcroft). Cecil Trouncer was Bosola. Edmund Wilson was perhaps the first to note that the play struck an audience differently in the wake of the revelation of the Holocaust; this note is, from 1945 on, continually struck in discussions of the appropriateness of Webster for the modern age. A 1946 production on Broadway did not fare as well; Rylands attempted to duplicate his London staging with John Carradine as Ferdinand and Elisabeth Bergner as the Duchess. W. H. Auden adapted Webster's text for the modern audience. However, the production's most notable innovation was in the character of Bosola, which was played by Canada Lee in whiteface. The production received savage reviews from the popular press, and it fared little better in the literary reviews.
The first successful postwar performance in America was staged at the off-Broadway Phoenix Theatre in 1957. Directed by Jack Landau, who had earlier staged a brief but well-reviewed White Devil, the production emphasised (and succeeded as) Grand Guignol. As Walter Kerr put it, "Blood runs right over the footlights, spreads slowly up the aisle and spills well out into Second Avenue."
Ashcroft returned as the Duchess in a 1960 production at the Aldwych Theatre. The play was directed by Donald McWhinnie; Eric Porter played Ferdinand and Max Adrian the Cardinal. Patrick Wymark played Bosola. The production received generally favourable but lukewarm reviews. In 1971, Clifford Williams directed the play for the Royal Shakespeare Company. Judi Dench took the title role, with Geoffrey Hutchings as Bosola and Emrys James as the Cardinal. Dench's husband Michael Williams played Ferdinand, casting which highlighted the sexual element of the play's siblings.
In 1980, Adrian Noble directed the play at the Royal Exchange Theatre, Manchester. This production received excellent notices; it was transferred to London, where it won the London Drama Critic's Award for best play. Helen Mirren played the title role; Mike Gwilym played Ferdinand, and Bob Hoskins played Bosola. Pete Postlethwaite was Antonio. Mirren's performance received special acclaim.
The actor-centered troupe led by Ian McKellen and Edward Petherbridge chose Webster's play as one of their first productions. The production opened in January 1986 in the Lyttelton Theatre of the Royal National Theatre and was directed and designed by Philip Prowse. The staging was highly stylised, the scenic backdrop segmented, and the actors' movements tightly controlled. The result, as Jarka Burian noted, was "a unified, consistent mise-en-scene...without enough inner turbulence to create a completely satisfying theatre experience." Eleanor Bron played the Duchess; McKellen played Bosola, Jonathan Hyde Ferdinand, and Petherbridge the Cardinal.
In 2010, the production was staged for Stage on Screen at the Greenwich Theatre, London. It was directed by Elizabeth Freestone and starred Aislin McGuckin in a production that set the play in the first half of the twentieth century. In The Guardian, the reviewer noted that 'Much of the pleasure of this revival lies in re-encountering Webster's language...full of savage poetry.' The production is now available on DVD.
In July 2010, English National Opera and Punchdrunk collaborated to stage the production, which had been commissioned by the ENO from composer Torsten Rasch. The production was staged in a promenade style and performed at a mysterious vacant site at Great Eastern Quay in London's Royal Albert Basin.
From March to June 2012, London's Old Vic Theatre staged a production, directed by Jamie Lloyd and starring, amongst others, Eve Best. In January 2014, Shakespeare's Globe staged a production  directed by Dominic Dromgoole and starring Gemma Arterton as the Duchess, James Garnon as the Cardinal, David Dawson as Ferdinand, Alex Waldmann as Antonio, and Sean Gilder as Bosola. It was the first production performed in the Globe's Sam Wanamaker Playhouse. The production was filmed and broadcast on BBC4 on 25 May 2014. This production coincided with a representation of the aforementioned Theobald text of 1736 as part of the Globe's Read Not Dead series – directed by David Oakes.
In 2018, a production was staged in Stratford-upon-Avon by the Royal Shakespeare Company.