Donald Harrison Jr. was born in New Orleans on June 23, 1960, the son of Donald Harrison Sr., a folklorist and Mardi Gras Indian chief who masked as Big Chief of four different New Orleans tribes over his lifetime. The son was put into the tradition before he could have chosen it: he first masked at the age of two, as Little Chief of the Creole Wild West. That inheritance runs through everything he has recorded, but it did not come first in his professional training. He took up the alto saxophone at sixteen, studied at the New Orleans Center for the Creative Arts with Ellis Marsalis, and went on to the Berklee College of Music in Boston, where his fellow students included Terri Lyne Carrington, Kevin Eubanks and Greg Osby. He was already working professionally while still in high school.

His apprenticeship in New York ran through three bandleaders in quick succession: Roy Haynes, the organist Jack McDuff, and then Art Blakey, who hired him into the Jazz Messengers in 1982 alongside the trumpeter Terence Blanchard. The two of them took the chairs Wynton Marsalis and Branford Marsalis had just vacated, and the pianist on the first record they made together, Oh-By the Way, cut at Fendel Sound Studios on May 20, 1982, was Johnny O'Neal. Harrison stayed with Blakey for the run of albums that followed: New York Scene, taped live at Mikell's in New York in May 1984, Blue Night, recorded at Studio 44 in Monster, the Netherlands, on March 17, 1985, and the Sweet Basil and Ronnie Scott's live sets of the same period. Away from the Messengers he was being hired by musicians working a long way from hard bop. He plays alto and bass clarinet on the two volumes of Eric Dolphy & Booker Little Remembered Live at Sweet Basil, recorded on October 3 and 4, 1986 with Mal Waldron, Richard Davis and Ed Blackwell, and he is in the front line of Don Pullen's The Sixth Sense (Black Saint, recorded June 12 and 13, 1985) with Olu Dara and Fred Hopkins. In June 1985 he took the alto chair on Tony Williams's Foreign Intrigue for Blue Note.

Harrison and Blanchard left Blakey and co-led a quintet from 1983 to 1989. Its first record, New York Second Line, was cut on October 15 and 16, 1983 for George Wein's Concord-distributed imprint, with Mulgrew Miller on piano, Lonnie Plaxico on bass and Marvin "Smitty" Smith on drums. Discernment followed on the same label, then three albums for Columbia and CBS: Nascence, recorded at RCA Studio A in New York over four days in January 1986, Crystal Stair, cut in the same room in April 1987 with Cyrus Chestnut, Reginald Veal and Carl Allen and produced by Delfeayo Marsalis, and Black Pearl in January 1988. The band broke up in 1989, and Harrison began recording under his own name with Full Circle for Sweet Basil in 1990 and For Art's Sake, a Blakey tribute taped live at Birdland on November 9 and 10, 1990, on which the bassist is an eighteen-year-old Christian McBride.

Indian Blues, recorded on May 22 and 23, 1991 and issued by Candid the following year, is the record that turned his New Orleans inheritance into a working method rather than a biographical detail. It sets Mardi Gras Indian chants against a modern jazz rhythm section and Crescent City rhythm and blues, with Dr. John on piano and lead vocals, Cyrus Chestnut on piano, Carl Allen on drums, Big Chief Smiley Ricks on congas, and Donald Harrison Sr. himself singing lead on three tracks. Nine years later Harrison went further into the same material with Spirits of Congo Square, recorded at Ultrasonic Studios in New Orleans in January 1996 and released by Candid in 2000, where he fronts a New Orleans Legacy Ensemble containing Nicholas Payton, Marlon Jordan and Jamil Sharif on trumpets, Delfeayo Marsalis on trombone, Victor Goines on tenor and Adonis Rose on drums. In 1999 he was named Big Chief of the Congo Square Nation Afro-New Orleans Cultural Group, a title he still holds. He has explained in interviews that he prefers the Afro-New Orleans framing to the Mardi Gras Indian one because it matches how musicians in Cuba and Brazil describe their own African-derived traditions.

The commercial middle of his catalogue pulls hard in the other direction. The Power of Cool, produced by Creed Taylor for CTI with Chuck Loeb, Will Lee and Mark Egan, is an unapologetic smooth jazz record. The two Impulse! albums that followed are the ones that named his idea. Nouveau Swing, recorded at Clinton Studios in August 1996 with Reuben Rogers and Christian McBride splitting the bass chair, gives half its programme to the swing beat set against modern dance rhythms and half to Caribbean feels, and Free to Be (1999) widened it further, bringing in Eddie Palmieri and Mulgrew Miller on piano and Brian Lynch on trumpet. Alongside the jazz work he was on hip-hop records: he plays tenor saxophone and flute on a track of Digable Planets' Blowout Comb (1994), and, years earlier on a Brooklyn stoop, he had taught diction and phrasing to Christopher Wallace, later The Notorious B.I.G., a mentorship Harrison described in detail to NPR in 2010.

From 2002 he recorded a run of albums for the German label Nagel Heyer, several of them showcases for his nephew Christian Scott, then a teenager: Real Life Stories (2002), Kind of New for Candid the same year, and Paradise Found, taped in 2000 and issued in 2003. Heroes and Free Style, both cut at Avatar Studios in New York on December 1 and 2, 2002, put him in a trio with Ron Carter and Billy Cobham, the same three who recorded New York Cool live at the Blue Note in April 2005 and This Is Jazz there again for a 2011 release. He was a fixture of Eddie Palmieri's jazz bands across the same decades, on Palmas (1994), Arete (1995), Vortex (1996), El Rumbero del Piano (1998), the Grammy-winning Listen Here! (2005), the Brian Lynch/Eddie Palmieri Project's Simpático (2006) and Sabiduría (2017). Hurricane Katrina turned him toward teaching: he began hiring New Orleans high-school students into his own working bands, and he has taught at the College of William & Mary, at the New School in New York and through the Tipitina's Foundation internship programme, becoming artistic director of the Louis Armstrong Summer Jazz Camp in 2022. He appeared as himself in the HBO series Treme and in Spike Lee's documentary When the Levees Broke.

Since the 2010s his most consistent employers have been two collective bands. He replaced Craig Handy in the Cookers, the veterans' septet whose other members include Billy Harper, Cecil McBee, George Cables, Billy Hart, Eddie Henderson and David Weiss, first appearing on their Time and Time Again in 2014 and staying through The Call of the Wild and Peaceful Heart (2016) and Look Out! (2021). He also took a reed chair in the Headhunters, after guesting on their Evolution Revolution back in 2003, and has recorded Speakers in the House, Live from Brooklyn Bowl and The Stunt Man with them. Eddie Henderson's late Smoke Sessions leader dates, Be Cool (2018), Shuffle and Deal (2020) and Witness to History (2023), all have Harrison in the front line. Berklee gave him an honorary doctorate in 2021, and in 2022 the National Endowment for the Arts named him a Jazz Master with the A.B. Spellman Fellowship for Jazz Advocacy, citing both his playing and his work keeping New Orleans traditions alive. Congo Square Suite, issued in 2023, is his most ambitious attempt to write the two halves of his life into one score. Most recently he is a credited featured artist on Arturo O'Farrill & The Afro Latin Jazz Orchestra's The Original Influencers: Dizzy, Chano & Chico, nominated for Best Latin Jazz Album at the 68th Grammy Awards in 2026.

Harrison's alto is a hard-swinging, bebop-rooted instrument with a bright, cutting tone and a phrase shape that comes out of the Jazz Messengers finishing school, and for a player so identified with New Orleans he is remarkably at home in the New York post-bop language: the National Endowment for the Arts cited his hard-swinging improvisational style first of all when it made him a Jazz Master. What separates him from his young-lion contemporaries of the 1980s is that he treats New Orleans not as local colour but as source material with its own harmonic and rhythmic logic. Nouveau Swing, the concept he named on the 1997 Impulse! album of that title, sets the swing beat against rhythm and blues, hip-hop and Caribbean dance rhythms rather than layering one on top of the other, and it has proved elastic enough to carry him through smooth jazz dates, an electric band, hip-hop sessions and orchestral writing without any of them reading as a departure. His doubling matters too: he plays tenor and soprano as well as alto, took up the bass clarinet for the Eric Dolphy tribute sessions of 1986, and sings on his own records. As a teacher he has been unusually consequential, and the institutions have said so. The NEA's citation named Jon Batiste, Christian Scott aTunde Adjuah, Trombone Shorty and Esperanza Spalding as artists he mentored, and Berklee gave him an honorary doctorate in 2021. New Orleans's own critics have kept voting for him, with four Best Saxophonist awards at OffBeat magazine's Best of the Beat between 2017 and 2023, and Jazziz made him its Person of the Year in January 2007.