He started in New Orleans second-line culture and studied New Orleans secret tribal culture, under his father, Big Chief Donald Harrison Sr.[2] He began participating as a masked Mardi Gras Indian at the age of two years, with the title "Little Chief of the Creole Wild West.

[3][2] As a professional musician, Harrison worked with Roy Haynes and Jack McDuff, before joining Art Blakey and the Jazz Messengers with Terence Blanchard and recorded albums in a quintet until 1989.

[4] This was followed by an album that reached into Harrison's New Orleans heritage, with guest appearances by Dr. John and Cyrus Chestnut and chants by the Guardians of the Flame Mardi Gras Indians.

His group, Donald Harrison Electric Band, has recorded popular radio hits and has charted in the top ten of Billboard magazine.

He performs as a producer, singer, and rapper in traditional New Orleans jazz and hip hop genres with his group, The New Sounds of Mardi Gras.

Going to places like Cuba and Brazil, they always put Afro in front of things that are from their country but are a derivative of African culture.

[3] Harrison was in Spike Lee's HBO documentary, When the Levees Broke, and has appeared as himself in eleven episodes of the television series, Treme.

Harrison is "known for his hard-swinging improvisational style and the creation of 'Nouveau Swing,' a blend of jazz with R&B, hip-hop, rock, and soul.

As co-leader with Terence Blanchard With Art Blakey With Joanne Brackeen With The Headhunters With Eddie Henderson With the Brian Lynch/Eddie Palmieri Project With Eddie Palmieri With Don Pullen With Lonnie Smith With Esperanza Spalding With Jane Monheit With Larry Coryell "Live in Bahia