Pascal has also completed filming for another independent movie, American Primitive, about a gay couple who try to hide their relationship from family and neighbors in 1973, a few years following the Stonewall Riots.

A friend of his from high school (Idina Menzel's boyfriend at the time) mentioned Rent to him. On a whim, he auditioned and was cast as the HIV-positive rock Guitarist Roger Davis. His powerful tenor voice and his performance in Rent earned him a Tony nomination, a Theater World award, and an Obie Award. He left the show on November 2, 1997, but went on to reprise Roger when Rent opened in London.

On December 19, 1998, Pascal married Cybele Chivian. Cybele is the daughter of Eric S. Chivian, M.D., Director of the Center for Health and the Global Environment at Harvard Medical School, and the granddaughter of Writer Joseph Jay Deiss. The couple has two sons, Lennon Jay (born October 2001) and Montgomery Lovell (born February 2004).

Pascal made his film debut in SLC Punk! (1999), and also appeared in School of Rock (2003) and Temptation (2004). The audio for Temptation, a musical, was recorded live on set during filming.

Pascal felt that he was looked upon solely as a Broadway singer, and thus returned to his rock and roll roots with a solo recording contract on Sh-K-Boom Records, which was founded by his Aida costar, Sherie Rene Scott and her husband Kurt Deutsch. He has released two solo rock albums, Model Prisoner (2000), Civilian (2004), as well as a collaborative rock album Blinding Light (2008) with Pianist, Larry Edoff. He also contributed a cover of Billy Joel's "New York State of Mind" to the CD Broadway Cares: Home for the Holidays (2001), the end credits song, "Winter Light", from the movie Noel (2004), and the song "Perfect Place" on the album Listen which showcases songs written by adolescents who stutter (2009). In School of Rock, he played Theo, lead singer of the band No Vacancy, and sang on two songs on the Soundtrack.

The role helped Pascal gain fame on Broadway, and he was cast in the Elton John and Tim Rice musical Aida as the Egyptian general Radames with the original and final casts (former Rent castmate Idina Menzel would co-star as Amneris in 2001), and Kander and Ebb's Cabaret, closing the show as the Emcee (closing cast). He also participated in several charity performances, including Chess in 2003 (playing the American, Freddie Trumper), Hair in 2004 (singing "I Got Life"), and the 24 Hour Plays in 2005. He returned to Aida in 2004 to close the run of the show as Radames.

In late 2005, he, along with five others of the principal cast, reprised their roles in the film version of Rent, directed by Chris Columbus. Pop idol Justin Timberlake campaigned heavily to Columbus and the producers for the role of Roger, but Columbus insisted that only the original cast members could convey the true meaning of Rent. The film released on November 23, 2005.

Pascal had a guest role as Dennis Hofferman, a murder victim, on an episode of Cold Case, with Tracie Thoms, his co-star from the film version of Rent, and Laura Bell Bundy, another Broadway star who originated the role of Elle Woods in Legally Blonde. The episode, called "Willkommen", originally aired on April 2, 2006, and revolved around an amateur production of Cabaret.

Along with original Broadway Rent cast member Anthony Rapp (Mark Cohen), Pascal returned to Broadway to star as Roger in Rent from July 30 to October 7, 2007. In January 2009, he and Rapp reprised their originating (and film) roles as Roger and Mark in another Rent tour titled: "Rent: The Broadway Tour", which played in many cities in the North America, as well as stops in Japan and South Korea. At the tour's Detroit, Michigan stop in February, Pascal suffered two herniated discs in his neck and was on medical leave for a week. Cary Shields, an understudy and also a Broadway Rent veteran, filled in. Pascal made a full recovery and finished up the tour in early 2010. This tour closed on February 7, 2010.

In the independent movie Falling Star (formerly titled Goyband), Pascal stars as a former boy-band icon who is booked to play a show at a Kosher hotel, but ends up shocking the guests with his sexy show. Fans were invited to participate in the movie as extras for the concert scenes. His co-stars are Amy Davidson, Cris Judd, Tovah Feldshuh, Dean Edwards, Tibor Feldman and Natasha Lyonne. Goyband originally premiered at the Jerusalem Films Festival in December 2008. Its North America premiere was July 2009, on Long Island. The movie was bought by distributor, MarVista Entertainment, which retitled it Falling Star.

As of 2009 and later, Pascal is developing a theatrical stage version of the classic 1988 concept album, Operation: Mindcrime by the progressive metal band, Queensrÿche. The band is one of Pascal's musical influences, and has fully endorsed his efforts.

Pascal joined the Broadway cast of Memphis on October 25, 2011 as Huey Calhoun. He replaced original cast member Chad Kimball in the role. He remained in the "Memphis" cast until the show's closure on August 5, 2012.

Beginning April 8, 2013, Pascal starred as Billy Flynn in the long-running Broadway revival of Chicago. His last performance as Billy was June 16, 2013.

In 2015, Pascal starred in Alleluia! The Devil's Carnival as The Agent, one of God's top generals in Heaven.