In 1985, he joined Sting, singer and bassist of rock band the Police, he played at Live Aid on the 13th of July. on his first solo project, The Dream of the Blue Turtles, alongside jazz and session musicians Omar Hakim on drums, Darryl Jones on the bass and Kenny Kirkland on keyboards. He became a regular in Sting’s line-up both in the studio and live up until the release of Brand New Day in 1999.

In 1986, Marsalis formed the Branford Marsalis Quartet with pianist Kirkland, drummer Jeff “Tain” Watts and bass player Robert Hurst. That year, they released their first album, Royal Garden Blues. That lineup of the quartet would go on to release four more albums, the last of which, I Heard You Twice the First Time (1992), won the Grammy Award for Best Instrumental Jazz Album, Individual or Group.

In 1988, Marsalis co-starred in the Spike Lee film School Daze, also rendering several horn-blowing interludes for the music in the film. His witty comments have pegged him to many memorable one-liners in the film. In 1989, Marsalis played a 30 second cover of “Lift Every Voice and Sing” over the opening logos of Lee’s film Do the Right Thing.

Between 1990 and 1994, Branford played with the Grateful Dead numerous times, and appeared on their 1990 live album Without a Net.

In 1992, Marsalis became the leader of the Tonight Show Band on the newly-launched The Tonight Show with Jay Leno, after Jay Leno replaced Johnny Carson. Initially, Marsalis turned down the offer, but later reconsidered and accepted the position. He brought with him the three other members of the Branford Marsalis Quartet, who became the Tonight Show Band’s pianist, drummer and bass player, respectively.

In 1994, Marsalis formed the group Buckshot LeFonque (named after a pseudonym once used by Cannonball Adderley), a jazz group with elements of rock and hip-hop. That year, they released their first album, Buckshot LeFonque, which was mostly produced by DJ Premier.

In 1994, Marsalis appeared on the Red Hot Organization’s compilation CD, Stolen Moments: Red Hot + Cool. The album, meant to raise awareness of the AIDS epidemic in African American society, was named Album of the Year by Time.

In 1995, Marsalis left The Tonight Show, having become unhappy in the role: he disliked that he was supposed to always show enthusiasm, even for jokes he thought were unfunny. He was succeeded as bandleader by guitarist Kevin Eubanks. In a well-publicized interview soon after leaving, Marsalis said, “The job of musical director I found out later was just to kiss the ass of the host, and I ain’t no ass kisser.” He also complained that when he did not laugh or smile, some viewers’ perception was, “Oh, he’s surly. He hates his boss.” When the interviewer asked if Marsalis did hate Leno, Marsalis responded, “Oh, I despised him.” He later stated that he did not hate Leno, and that this was a sarcastic response to what he considered “a ridiculous question”.

In 1997, bassist Eric Revis replaced Hurst in the Branford Marsalis Quartet. Kirkland died the following year, and was replaced by pianist Joey Calderazzo. The Branford Marsalis Quartet has since toured and recorded extensively. For two decades Marsalis was associated with Columbia, where he served as creative consultant and producer for jazz recordings between 1997 and 2001, including signing saxophonist David S. Ware for two albums.

In 2002, Marsalis founded his own label, Marsalis Music. Its catalogue includes Claudia Acuña, Harry Connick Jr., Doug Wamble, Miguel Zenón, in addition to albums by members of the Marsalis family.

Marsalis has also become involved in college education, with appointments at Michigan State University (1996–2000), San Francisco State University (2000–2002), and North Carolina Central University (2005–present). After Hurricane Katrina in 2005, Marsalis and Harry Connick, Jr., working with the local Habitat for Humanity, created Musicians Village in New Orleans, with the Ellis Marsalis Center for Music the centerpiece.

Marsalis and the members of his quartet joined the North Carolina Symphony for American Spectrum, released in February 2009 by Sweden’s BIS Records. The album showcases Marsalis and the orchestra performing a range of American music by Michael Daugherty, John Williams, Ned Rorem and Christopher Rouse, while being conducted by Grant Llewellyn.

On July 14, 2010, Marsalis made his debut with the New York Philharmonic on Central Park’s Great Lawn. Led by conductor Andrey Boreyko, Marsalis and the New York Philharmonic performed Glazunov’s “Concerto for Alto Saxophone” and Schuloff’s “Hot-Sonate for Alto Saxophone and Orchestra.” Boreyko, Marsalis and the Philharmonic performed the same program again in Vail, CO later that month and four more times at Avery Fisher Hall in New York, NY the following February.

In June 2011, after working together for over 10 years in a band setting, Branford Marsalis and Joey Calderazzo released their first duo album titled Songs of Mirth and Melancholy, on Branford’s label, Marsalis Music. Their first public performance was at the 2011 TD Toronto Jazz Festival.

In 2012, Branford Marsalis released Four MFs Playin’ Tunes on deluxe 180-gram high definition vinyl, prior to Record Store Day 2012 on April 21, 2012. This is the first recording of the Branford Marsalis Quartet with drummer Justin Faulkner, who joined the band in 2009, and was the first vinyl release from Marsalis Music. The album was named Apple iTunes Best of 2012 Instrumental Jazz Album of the Year.

In 2019 Marsalis released The Secret Between the Shadow and the Soul, which he recorded in Australia with his quartet. Marsalis, commenting on the longevity of his band and their approach said, ahead of the album’s release: ‘“Staying together allows us to play adventurous, sophisticated music and sound good. Lack of familiarity leads to defensive playing, playing not to make a mistake. I like playing sophisticated music, and I couldn’t create this music with people I don’t know.”