Nicholas Payton was born September 26, 1973, in New Orleans, Louisiana, the son of bassist and sousaphonist Walter Payton. He began playing trumpet at four, and by nine was sitting in with the Young Tuxedo Brass Band alongside his father. At ten he was already working professionally, as a member of trumpeter James Andrews's All-Star Brass, and guitarist and banjoist Danny Barker gave him his first steady gig at the Famous Door on Bourbon Street. He trained formally at the New Orleans Center for Creative Arts and then at the University of New Orleans, absorbing the city's brass band tradition directly from its working elders rather than only from records.

In the early 1990s Payton toured with pianist Marcus Roberts and drummer Elvin Jones, recording as a sideman on Jones's Youngblood (1992, Enja), Going Home (1993) and It Don't Mean a Thing (1994). In 1993 he appeared on New Orleans Collective, the debut of a co-led group with saxophonist Wessell Anderson, bassist Christopher Thomas, pianist Peter Martin and drummer Brian Blade. He then signed with Verve Records, releasing his leader debut From This Moment in 1995 (recorded 1994) and following it a year later with Gumbo Nouveau, a quintet date with Tim Warfield and Anthony Wonsey. In 1996 he appeared on the soundtrack to Robert Altman's film Kansas City. In 1997 he won the Grammy Award for Best Jazz Instrumental Solo for his playing on "Stardust," from Doc Cheatham & Nicholas Payton, a duo studio album pairing the 23-year-old Payton with the 92-year-old trumpet elder Doc Cheatham; the same record earned a second Grammy nomination for Best Jazz Instrumental Performance, Individual or Group. He continued the Verve run with Payton's Place (1998) and Nick@Night (1999), then closed it out with the big-band Louis Armstrong tribute Dear Louis (2001, recorded 2000), a Grammy nominee for Best Large Jazz Ensemble Album featuring his father Walter Payton on bass alongside Peter Bernstein and Vincent Gardner.

Payton moved to Warner Bros. Records in 2003 for Sonic Trance, an electronic-tinged fusion date that brought a Grammy nomination for Best Contemporary Jazz Album and introduced his touring band of the same name. In 2004 he became a founding member of the SFJAZZ Collective, serving as a member of its inaugural band alongside tenor saxophonist Joshua Redman through 2006. He recorded the Wayne Shorter tribute Mysterious Shorter (2006, Chesky) as co-leader with organist Sam Yahel, then released Into the Blue (2008, Nonesuch), on which he played trumpet, sang and handled synthesizers himself. In 2008 and 2009 he toured and recorded as a member of the Blue Note 7, a septet including Ravi Coltrane and Peter Washington assembled to mark Blue Note Records' 70th anniversary, documented on Mosaic: A Celebration of Blue Note Records (2009).

In 2011 Payton released Bitches, on which he wrote, sang and played every instrument himself, and formed a 21-piece ensemble he called the Television Studio Orchestra. In 2012 the Czech National Symphony Orchestra commissioned and premiered his first full orchestral work, The Black American Symphony. In 2013 he founded his own label, BMF Records, releasing #BAM: Live at Bohemian Caverns, on which he frequently plays trumpet and Fender Rhodes simultaneously, and Sketches of Spain, recorded with the Basel Symphony Orchestra in Switzerland. Around this period Payton became known as an outspoken commentator on jazz historiography, arguing over more than a decade of interviews and writing that the music should be called "Black American Music," or BAM, rather than "jazz," a term he has criticized as a historically diminishing label imposed from outside the tradition; the position has made him one of the more prominent and polarizing voices in modern jazz criticism.

Payton launched his own Paytone Records imprint and released a steady run of albums through the following decade: Numbers (2014) and Letters (2015), a two-disc set with bassist Vicente Archer and drummer Bill Stewart, Textures (2016), and the two-disc Afro-Caribbean Mixtape (2017). Relaxin' with Nick (2019, Smoke Sessions) was a career-spanning double set, followed by the pandemic-era Quarantined with Nick and Maestro Rhythm King (both 2020). Smoke Sessions (2021) paired him in trio with bassist Ron Carter and saxophonist George Coleman, and The Couch Sessions followed in 2022. That same year he was one of five co-credited leaders, alongside drummer Terri Lyne Carrington, pianist Kris Davis, bassist Linda May Han Oh and guitarist Matthew Stevens, on New Standards, Vol. 1 (Candid), a songbook album drawn entirely from compositions by women; it won the Grammy Award for Best Jazz Instrumental Album in 2023. He released Drip in 2023 and, in 2025, Triune, a three-way collaboration with Esperanza Spalding and drummer Karriem Riggins issued under his own name.

In 2024 Payton was named chair of the Brass Department at Berklee College of Music. In 2025, following renewed public attention to past statements, some dating to 2010, that critics characterized as antisemitic, Berklee ended his appointment as department chair; Payton has disputed the characterization of his remarks and said he was not given a formal review process before the decision.

Payton built his voice on a New Orleans brass foundation absorbed directly from elders like his father and Danny Barker, then extended it with the harmonic vocabulary of modern post-bop trumpet; his 1997 Grammy-winning duo record with the 92-year-old Doc Cheatham made that generational bridge explicit on record. He is unusual among trumpeters for his fluency on keyboards, playing full arrangements on Fender Rhodes and piano, sometimes on the same track as his own trumpet lines, and for leader albums, such as Bitches, on which he performs every part himself. Beyond the horn, Payton has become one of jazz's most-discussed critical voices for his insistence that the music be called "Black American Music" rather than "jazz," an argument about naming, ownership and historical erasure that he has pressed consistently since the early 2010s and that has drawn both serious critical engagement and public controversy.