He studied acting and began writing musicals at Adelphi University, from which he graduated with honors in 1982. His first professional musical was to be an adaptation of George Orwell's novel 1984, but he was unable to obtain the rights and instead created his own version of a dystopian future and called it Superbia. The show was never produced, but it did have a concert performance at the Village Gate nightclub in Greenwich Village in September 1989.

Larson next worked on a musical called tick, tick...BOOM!, which was written as a one-man show, and he performed it in New York in the early '90s. As he worked his way up in the New York theater community, he won the Richard Rodgers Production Award, the Richard Rodgers Development Grant, the Stephen Sondheim Award, and the Gilman & Gonzalez-Falla Theatre Foundation's Commendation Award. He wrote the music for J.P. Morgan Saves the Nation, for the children's television series Sesame Street, and for the children's book-cassettes An American Tail and Land Before Time. He also conceived, directed, and wrote songs for a children's video, Away We Go! His musical Rent, loosely based on Henri Murger's Scenes de la Vie de Bohème (also the source of Puccini's opera La Bohème a century earlier) and set in the present among HIV-positive artists living on New York's Lower East Side, was accepted for a production by the off-off-Broadway New York Theater Workshop in 1992, and after years of development began to gain attention when it went into rehearsals in December 1995.

Larson died suddenly at the age of 35 on January 25, 1996, of an undiagnosed aortic aneurysm later thought to have been caused by Marfan Syndrome. Nevertheless, Rent began previews the following night and opened to rapturous reviews on February 13, 1996. Larson was posthumously awarded the Pulitzer Prize for Drama, and the production won Obie Awards for Outstanding Book, Music, and Lyrics as well as the Outer Critics Circle Award for Best Musical. Rent transferred to Broadway, opening at the Nederlander Theatre on April 29, 1996. It won six Drama Desk Awards, including Outstanding Musical, Outstanding Book of a Musical, Outstanding Music and Outstanding Lyrics; the New York Drama Critics Circle Award for Best Musical; and four Tony Awards, including Best Musical, Best Book of a Musical, and Best Original Score of a Musical. The original Broadway cast album released by DreamWorks Records on August 27, 1996, reached the Top 20 and sold over two million copies. The song "Seasons of Love" from the score became a popular standard recorded by Madeline Bell, Michael Ball, Betty Buckley, Petula Clark, and Johnny Mathis, among others.

In 2001, Larson's unproduced musical tick, tick...BOOM! was finally given a production off-Broadway, and RCA recorded it for an original cast album. Rent was adapted into a motion picture that opened in 2005. The soundtrack album reached the Top 40, as did its recording of "Seasons of Love," released as a single. Meanwhile, the Broadway production of Rent, having spawned national tours and international productions, continued to play year after year. In November 2007, PS Classics released Jonathan Sings Larson, an album of demo recordings by Larson of songs from Rent, tick, tick...BOOM!, and Superbia, plus other compositions. On January 15, 2008, it was announced that Rent would close on Broadway on June 1, 2008, after more than 12 years of continuous performances, by which time it would be the seventh longest-running musical in Broadway history. Due to increased ticket demand, the show was later extended to September 7, 2008. ~ William Ruhlmann