Toward the close of 1919, the prominent theatrical producer Sam H. Harris made a proposition to his friend Irving Berlin: if the popular songwriter would devise a musical revue, Harris would find a theatre for it. Berlin responded with The Music Box Revue and in 1920 the Music Box Theatre was built to house the show. The Shuberts began acquiring shares of the venue from Harris in the 1920s. When Harris died in 1941, his wife sold half the shares in the theatre to the Shuberts, and half to Berlin. From that point on, Berlin and Shubert became equal partners in the ownership of the house. In 2007, the Berlin share of the theatre was sold to Shubert, now the sole owner of the theatre.

The Music Box Revue opened the theatre glamorously in September 1921, and for each of the next four years, Berlin created an entirely new edition of the show. The theatre then became home to a number of non-musicals starting with Cradle Snatchers (1925), which featured a young Humphrey Bogart, Chicago (1926) — later adapted into a musical by Kander and Ebb, and Philip Barry’s Paris Bound (1927). Cole Porter’s musical Paris (1928) and the musical revue The Little Show (1929) closed out the decade.

The 1930s at the Music Box were George S. Kaufman and Moss Hart’s decade. Their show Once in a Lifetime (1930) was followed by Merrily We Roll Along (1934)—later adapted into a musical by Stephen Sondheim, First Lady (1935), I’d Rather Be Right (which transferred here from the Alvin in 1938), and The Man Who Came to Dinner (1939). Kaufman (with Morrie Ryskind) penned the book for the Gershwin musical Of Thee I Sing (1931), which became the first musical to win the Pulitzer Prize. Kaufman also collaborated with Edna Ferber on a number of productions in the 1930s, beginning with Dinner at Eight (1932), followed by Stage Door (1936) and The Land Is Bright (1941), and directed John Steinbeck’s Of Mice and Men (1937). Hart collaborated with Irving Berlin on As Thousands Cheer (1933).

A number of notable theatre artists had shows at the Music Box in the 1940s and 1950s. Mike Todd’s Star and Garter (1942) included music by Irving Berlin and featured Gypsy Rose Lee. Rodgers and Hammerstein produced I Remember Mama (1944), whose cast included a young Marlon Brando making his Broadway debut. Brando returned to the theatre in A Flag is Born (1946) by Kurt Weill, whose Lost in the Stars (1949) also premiered here. Other significant productions include three William Inge plays: Picnic (1953), Bus Stop (1955), and The Dark at the Top of the Stairs (1957); Separate Tables (1956), an adaptation of Rashomon (1959) and Peter Shaffer’s Five Finger Exercise (1959).

Many distinguished playwrights of the 20th century premiered works at the Music Box, including Arthur Laurents’s Invitation to a March (1960) and Harold Pinter’s The Homecoming (1967). The 1970s were a decade of mystery, with Anthony Shaffer’s Sleuth (1970) and Deathtrap (1978) both running over one thousand performances. Other shows of the 70s and 80s include Alan Ayckbourn’s Absurd Person Singular (1974), the musical revue Side by Side by Sondheim (1977), Agnes of God (1982) with Amanda Plummer, and the Shubert co-production of Les Liaisons Dangereuses (1987) starring Alan Rickman and Lindsay Duncan.

In the 1990s productions at the playhouse included the musical Blood Brothers (1993), a theatrical adaptation of the Rodgers and Hammerstein film State Fair (1996) — producer David Merrick’s last show, Closer (1999) starring Natasha Richardson, and a revival of Peter Shaffer’s Amadeus (1999).

More recently the Music Box was home to the Shubert production of Michel Legrand’s Amour (2002), and a revival of Tennessee Williams’s Cat on a Hot Tin Roof (2003) with Ashley Judd and Ned Beatty. Julianne Moore made her Broadway debut at the Music Box in David Hare's The Vertical Hour (2006) and Angela Lansbury returned to Broadway here in Terrence McNally's Deuce (2007) with Marian Seldes. The theatre also premiered Tony and Pulitzer Prize winning August: Osage County playwright Tracy Lett’s Superior Donuts (2009), and then offered a revival of Lend Me A Tenor (2010).

Because of its dainty, jewel-like qualities, the Music Box Theatre is aptly named. Designed by architect Charles Howard Crane in collaboration with E. George Kiehler, it was built in the neo-Georgian style, more in the manner of a dignified manor or country home than in the typical theatrical style of most other Broadway playhouses.