Leonard was born Robert Lawrence Leonard in Jersey City, New Jersey, the son of Joyce P. (née Peterson), a nurse, and Robert Howard Leonard, a teacher of Spanish. He grew up in Ridgewood, where he attended Ridgewood High School before moving on to Fordham University and later Columbia University School of General Studies and Continuing Education (GS). Because he shares his birth name with another actor, he uses the name of his brother Sean for his Screen Actors Guild membership.

Leonard received rave reviews for his role in the 1997, Christopher Reeve-directed film, In the Gloaming. Entertainment Weekly said that, in the film, Leonard "does a first-rate job of juggling Danny's mixture of despair, neediness, and mordant jokiness."

He is a three-time Tony Award nominee (1993, 2001 and 2003), winning in 2001 (Best Actor - Featured Play) for his role as A.E. Housman in Tom Stoppard's The Invention of Love. He also played Romeo Off Broadway in Romeo and Juliet at the Riverside Shakespeare Company in 1988.

Since 2004, he has played Dr. James Wilson, head of the oncology department, on the FOX TV series House. In 2007, Leonard appeared on Entertainment's Weekly's 100 list as "Dr. Underrated."

Leonard maintains a good friendship with House co-star Hugh Laurie, as well as childhood friend, Dead Poets Society and Tape co-star, Ethan Hawke with whom he founded the Malaparte theater company, along with James Waterston, Steve Zahn, and Frank Whaley.

Robert Sean Leonard (2001) · Frank Langella (2002) · Denis O'Hare (2003) · Brían F. O'Byrne (2004) · Liev Schreiber (2005) · Ian McDiarmid (2006) · Billy Crudup (2007) · Jim Norton (2008) · Roger Robinson (2009) · Eddie Redmayne (2010)

Complete list: (1947–1975) · (1976–2000) · (2001–present)