The play was premiered on 3 April 1957 at the Royal Court Theatre, London, directed by Roger Blin, who also played Hamm; Jean Martin was Clov, Georges Adet was Nagg and Christine Tsingos was Nell. In the early 1960s, an English language production produced by Philippe Staib and, directed by Beckett himself with Patrick Magee and Jack MacGowran was staged at the Studio des Champs-Elysees, Paris. Other early productions were those at the Cherry Lane Theatre, New York, 28 January 1958, directed by Alan Schneider with Lester Rawlins as Hamm, Alvin Epstein as Nagg and Gerald Hiken playing Clov (a recording of the play, with P. J. Kelly replacing Epstein, was released by Evergreen Records in 1958); and at the Royal Court directed by George Devine who also played Hamm, with Jack MacGowran as Clov.
After the Paris production, Beckett himself directed two other productions of the play: at the Schiller Theater Werkstatt, Berlin, 26 September 1967, with Ernst Schröder as Hamm and Horst Bollmann as Clov; and at the Riverside Studios, London, May 1980 with Rick Cluchey as Hamm and Bud Thorpe as Clov.
In 1984, JoAnne Akalaitis directed the play at the American Repertory Theatre in Cambridge, Massachusetts. The production featured music from Philip Glass and was set in a derelict subway tunnel. Grove Press, the owner of Beckett's work, took legal action against the theatre. The issue was settled out of court through the agreement of an insert into the program, part of which was written by Beckett himself:
Any production of Endgame which ignores my stage directions is completely unacceptable to me. My play requires an empty room and two small windows. The American Repertory Theater production which dismisses my directions is a complete parody of the play as conceived by me. Anybody who cares for the work couldn't fail to be disgusted by this.
In 2005, Tony Roberts starred as Hamm in a revival directed by Charlotte Moore at the Irish Repertory Theater in New York City with Alvin Epstein as Nagg, Adam Heller as Clov and Kathryn Grody as Nell.
In 2008 there was a brief revival staged at the Brooklyn Academy of Music starring John Turturro as Hamm, Max Casella as Clov, Alvin Epstein as Nagg and Elaine Stritch as Nell. New York theatre veteran Andrei Belgrader directed, replacing originally sought Sam Mendes at the helm of the production.
The British theatre company Complicite staged the play in London's West End with Mark Rylance as Hamm and Simon McBurney (who also directed the production) as Clov. The production also featured Tom Hickey as Nagg and Miriam Margolyes as Nell. The production opened on 2 October 2009 at the Duchess Theatre. Tim Hatley designed the set.
In 2010, Steppenwolf Theatre Company staged Endgame. It was directed by Frank Galati and starred Ian Barford as Clov, William Petersen as Hamm, Francis Guinan as Nagg, and Martha Lavey as Nell. James Schuette was responsible for set and scenic design.
In 2015, two of Australia's major state theatre companies staged the play. For Sydney Theatre Company, Andrew Upton directed the production, featuring Hugo Weaving as Hamm  and for Melbourne Theatre Company, Colin Friels starred in a production directed by Sam Strong and designed by visual artist Callum Morton.
In 2016, Coronation Street actors David Neilson and Chris Gascoyne starred in a staging of the play at both the Citizens Theatre in Glasgow and HOME in Manchester.
The Old Vic in London announced that in January 2020, Alan Cumming and Daniel Radcliffe will star in a production of the play in a double bill with Rough for Theatre II.