The son of writer and longtime Reader's Digest editor Daniel O'Keefe, Laurence O'Keefe was studying anthropology at Harvard University when he started writing for The Harvard Lampoon. His foray into musical theater came via the storied Hasty Pudding Theatricals. In addition to performing with the organization, he composed music for shows including Suede Expectations, which featured a book by Mo Rocca. After graduating in 1991, he studied scoring at the Berklee College of Music and USC.
O'Keefe had his first minor hit with the irreverent Bat Boy: The Musical, which premiered in Los Angeles in 1997. With a book by Keythe Farley and Brian Flemming based on a tabloid story from the early '90s, it ran off-Broadway from March to December 2001 before making its West End debut at the Shaftesbury Theatre in 2004. Winner of the Jonathan Larson Performing Arts Foundation Award during its off-Broadway run, Bat Boy also won O'Keefe the 2004 Kleban Prize for lyrics, which included a substantial cash prize. In the meantime, the musical became a popular regional theater selection across the U.S. and was performed at the Edinburgh Fringe Festival, among other productions abroad.
A collaboration with his wife and fellow Hasty Pudding alum Nell Benjamin, the musical comedy Legally Blonde: The Musical was O'Keefe's next high-profile production. An adaptation of the 2001 film, it opened in San Francisco in January 2007, moving to Broadway's Palace Theatre that April. O'Keefe and Benjamin were nominated for the Tony Award for Best Original Score, also receiving Drama Desk Award nominations for both music and lyrics. A West End production of Legally Blonde reached London in 2010.
For his next musical, O'Keefe collaborated with TV writer/producer and Reefer Madness lyricist Kevin Murphy. Featuring O'Keefe's music and Murphy's book and lyrics, Heathers: The Musical, an adaptation of the 1988 high-school black comedy, premiered in Los Angeles in 2013. It opened off-Broadway the following year and on the West End in 2018. A cast recording of the London production followed on Ghostlight in 2019.