After touring with Marcus Roberts and Elvin Jones in the early ’90s, Payton signed a contract with Verve Records; his first album, From This Moment, appeared in 1995. In 1996 he performed on the soundtrack of the movie Kansas City, and in 1997 received a Grammy Award (Best Instrumental Solo) for his playing on the album Doc Cheatham & Nicholas Payton.

After seven albums on Verve, Payton signed with Warner Bros. Records, releasing Sonic Trance, his first album on the new label, in 2003. Besides his recordings under his own name, other significant collaborations include Trey Anastasio, Ray Brown, Ray Charles, Daniel Lanois, Dr. John, Stanley Jordan, Herbie Hancock, Roy Haynes, Zigaboo Modeliste, Marcus Roberts, Jill Scott, Clark Terry, Allen Toussaint, Nancy Wilson, Dr. Michael White, and Joe Henderson.

In 2004, he became a founding member of the SFJAZZ Collective. In 2008, he joined The Blue Note 7, a septet formed in honor of the 70th anniversary of Blue Note Records. In 2011, he formed a 21-piece big band ensemble called the Television Studio Orchestra. In 2011, he also recorded and released Bitches, a love narrative on which he played every instrument, sang, and wrote all of the music. In 2012 the Czech National Symphony Orchestra commissioned and debuted his first full orchestral work, The Black American Symphony. And in 2013, he formed his own record label, BMF Records, and the same year released two albums, #BAM Live at Bohemian Caverns, where he plays both trumpet and Fender Rhodes, often at once, and Sketches of Spain, which he recorded with the Basel Symphony Orchestra in Switzerland.