Toussaint grew up in a shotgun house in the New Orleans neighborhood of Gert Town, where his mother, Naomi Neville (whose name he later adopted pseudonymously for some of his works), welcomed and fed all manner of musicians as they practiced and recorded with her son. After a lucky break at age 17 in which he stood in for Huey Smith at a performance with Earl King's band in Prichard, Alabama, Toussaint was introduced to a group of local musicians who performed regularly at a night club on LaSalle street Uptown; they were known as the Dew Drop Set. He initially recorded for RCA Victor as Al Tousan and recorded an album of instrumentals, including the song "Java", which became a #1 hit for Al Hirt (also on RCA) in 1964.
A significant early influence on Toussaint was the second-line piano style of Professor Longhair. In his early years he worked mainly for Joe Banashak's Minit Records and Instant Records, but after Minit was sold to its distributor, he teamed up with Marshall Sehorn, starting their own record label variously known as Tou-Sea, Sansu, Deesu or Kansu. In 1973 Toussaint and Sehorn created the Sea-Saint recording studio in Gentilly.
Toussaint credited about twenty songs credited to his parents. These pieces range from Benny Spellman's 1961 cover of "Fortune Teller" through The Artwoods' 1995 cover of "Work, Work, Work", and beyond (see Alison Krauss' and Robert Plant's 2007 cover of "Fortune Teller" on their collaboration album Raising Sand. A fairly thorough song list appears in Toussaint's discography section Pseudonyms, below.
Toussaint also launched his own solo career, which peaked in the '70s with the albums From a Whisper to a Scream and Southern Nights. It was during this time that he teamed with Labelle, and produced their highly acclaimed 1975 album Nightbirds, which spawned the Number One hit, "Lady Marmalade". The same year, Toussaint collaborated with Paul McCartney and Wings for their hit album Venus and Mars and played on the song Rock Show. Two years later, Glen Campbell covered Toussaint's "Southern Nights" and carried the song to Number One on the Pop, Country and Adult-Contemporary Charts. Along with many of his contemporaries, Toussaint found that interest in his compositions was rekindled when his work began to be sampled by hip hop artists in the 1980s and 1990s.
Toussaint performed a taping for the popular PBS series Austin City Limits on June 30, 2009 as part of the show's 35th anniversary season. He played instrumentals from his most recent album, "The Bright Mississippi", as well as many songs from his back catalog. He performed with Levon Helm and his band on Imus in the Morning on October 9, 2009. In December 2009, he was featured on Elvis Costello's Spectacle program on the Sundance Channel, singing "A Certain Girl". Toussaint appeared on Eric Clapton's 2010 album, Clapton, in two Fats Waller covers, "My Very Good Friend the Milkman" and "When Somebody Thinks You're Wonderful".
Toussaint is a musical mentor to Swedish-born New Orleans songwriter and performer Theresa Andersson.
Jerry Garcia Band performed "Get Out of My Life, Woman" during the 1980s and 1990s and a live version of that song is on the Jerry Garcia Band live album of 1991.
Jerry Garcia Band also recorded "I’ll Take a Melody" in 1976 for the album Reflections and performed it regularly during the 1970s, 1980s and 1990s. A live version of that song is on the Pure Jerry, After Midnight live album recorded in 1980.
The Doors' version of "Get Out Of My Life Woman" was recorded in 1967 but only released in 2008 on the CD release of Live at the Matrix.
Nils Landgren & Joe Sample covered "Get Out Of My Life Woman" and "With You In Mind" on the 2006 album Creole Love Song.
Gerry Rafferty recorded "Get Out of My Life Woman" in 1992 for his album On a Wing and a Prayer.
Three Dog Night covered "Play Something Sweet (Brickyard Blues)" on their 1974 album Hard Labor. It was also released as a highly successful single, surpassing that of Frankie Miller's version, released the same year.
The song 'I Feel Good' written under the pseudonym Naomi Neville and originally released in the US by Benny Spellman (1965), was a major hit in New Zealand for Larry's Rebels (1966) and later Citizen Band (Studio and live versions - 1978). It was recorded by Greg Anderson (Australia 1966), Chants R&B (New Zealand 1966 live recording, released 2008), The Artwoods (UK 1966 - Single on Decca by R&B band led by Art Wood, brother of Ron Wood. Members included Jon Lord, later of Deep Purple.), The Kuhtze Band (New Zealand 1987), The Gavin Burgess Band (1997 Live recording released 2012).
Le Show interviews & performances: Shearer, Harry (September 5, 2004). "le Show". HarryShearer.com. Retrieved January 3, 2009. Shearer, Harry (February 24, 2008). "le Show". HarryShearer.com. Retrieved January 3, 2009.