The original 1965 Broadway production ran for 2,328 performances and won five Tony Awards, including Best Musical. The musical has been revived four times on Broadway, becoming one of the most enduring works of musical theatre.

The signature song, "The Impossible Dream", became a standard. The musical has played in many other countries around the world, with productions in German, Hebrew, Japanese, Icelandic, Gujarati, Uzbekistani, Magyar, Slovenian, Swahili, Finnish, Ukrainian and nine distinctly different dialects of the Spanish language.

Man of La Mancha was first performed at the Goodspeed Opera House in Connecticut in 1964, and had its New York premiere on the thrust stage of the ANTA Washington Square Theatre in 1965.

Man of La Mancha started as a non-musical teleplay written by Dale Wasserman for CBS's DuPont Show of the Month program. This original telecast starred Lee J. Cobb, Colleen Dewhurst (who replaced Viveca Lindfors), and Eli Wallach, and was not performed on a thrust stage, but on a television sound stage. The DuPont Corporation disliked the title Man of La Mancha, thinking that its viewing audience would not know what La Mancha actually meant, so a new title, I, Don Quixote, was chosen. The play was broadcast live on November 9, 1959, with an estimated audience of 20 million.

Years after this television broadcast, and after the original teleplay had been unsuccessfully optioned as a non-musical Broadway play, director Albert Marre called Wasserman and suggested that he turn his play into a musical. Mitch Leigh was selected as composer, who in turn selected for his orchestrations Carlyle W. Hall. Contrary to what has been misstated here, Leigh did not write the orchestrations under the name of his company Music Makers; rather, it was actually Hall, who was his employee, and whose family retains the original orchestra ideas totally redone by Hall (a composition student of Tibor Serly and Béla Bartók, arranger for Arthur Godfrey's talent scouts).[citation needed] During the show's most recent Broadway revival in 2002, Leigh corrected history by reprinting all of the show's playbills and placing the name of Carlyle W. Hall Sr. in place of Music Makers, albeit posthumously for Hall. Several sources, however still credit Music Makers, Inc. with the orchestrations.

The score was unusual in its time, because the orchestra had no string instruments other than a double bass, but rather uses brass, woodwinds, percussion, and flamenco guitars.

The original lyricist of the musical was poet W. H. Auden, but his lyrics were discarded, some of them considered too overtly satiric and biting, attacking the bourgeois audience at times. Auden's lyrics were replaced by those of Joe Darion.

The musical first played at the Goodspeed Opera House in Connecticut in 1965. Rex Harrison was to be the original star of this production, but the musical demands of the role were heavy for him. After 21 previews, the musical opened at the ANTA Washington Square Theatre in Greenwich Village on November 22, 1965, then moved to Broadway at the Martin Beck Theatre on March 20, 1968, then to the Eden Theatre on March 3, 1971, and finally to the Mark Hellinger Theatre on May 26, 1971 for its last month, a total original New York run of 2,329 performances. Musical staging and direction were by Albert Marre, choreography was by Jack Cole, and Howard Bay was the scenic and lighting designer, with costumes by Bay and Patton Campbell.

Richard Kiley won a Tony Award for his performance as Cervantes/Quixote in the original production, and it made Kiley a bona fide Broadway star.

The original cast also included Irving Jacobson (Sancho), Ray Middleton (Innkeeper), Robert Rounseville (The Padre), and Joan Diener (Aldonza). John Cullum, José Ferrer, Hal Holbrook, and Lloyd Bridges also played Cervantes and Don Quixote during the run of the production.