The youngest of three children, Toussaint was born in 1938 in New Orleans and grew up in a shotgun house in the Gert Town neighborhood, 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.

In early 1958 he recorded an album of instrumentals, The Wild Sound of New Orleans, with a band including Alvin "Red" Tyler (baritone sax), either Nat Perrilliat or Lee Allen (tenor sax), either Justin Adams or Roy Montrell (guitar), Frank Fields (bass), and Charles "Hungry" Williams (drums).

[8] The recordings included Toussaint and Tyler's composition "Java", which first charted for Floyd Cramer in 1962 and became a number 4 pop hit for Al Hirt (also on RCA) in 1964.

[11][12][13] A two-sided 1962 hit by Benny Spellman comprised "Lipstick Traces (on a Cigarette)" (covered by The O'Jays, Ringo Starr, and Alex Chilton) and the simple but effective "Fortune Teller" (covered by various 1960s rock groups, including The Rolling Stones, The Nashville Teens, The Who, The Hollies, The Throb, and The Searchers founder Tony Jackson).

[11][14][15] "Ruler of My Heart", written under his pseudonym Naomi Neville, first recorded by Irma Thomas for the Minit label in 1963, was adapted by Otis Redding under the title "Pain in My Heart" later that year, prompting Toussaint to file a lawsuit against Redding and his record company, Stax (the claim was settled out of court, with Stax agreeing to credit Naomi Neville as the songwriter).

The song was released again in 1980 by Warren Zevon, as the single from the album Bad Luck Streak in Dancing School; it reached 57 on Billboard's Hot 100.

[23] Their backing can be heard in songs such as Dorsey's "Ride Your Pony" and "Working in the Coal Mine", sometimes augmented by horns, which were usually arranged by Toussaint.

[24] The Toussaint-produced records of these years backed by the members of the Meters, with their increasing use of syncopation and electric instrumentation, built on the influences of Professor Longhair and others before them, but updated these strands, effectively paving the way for the development of a modern New Orleans funk sound.

As part of a process begun at Sansu and reaching fruition in the 1970s, he developed a funkier sound, writing and producing for a host of artists, such as Dr. John (backed by the Meters, on the 1973 album In the Right Place, which contained the hit "Right Place, Wrong Time") and an album by The Wild Tchoupitoulas, a New Orleans Mardi Gras Indians tribe led by "Big Chief Jolly" (George Landry) (backed by the Meters and several of his nephews, including Art and Cyril Neville of the Meters and their brothers Charles and Aaron, who later performed and recorded as The Neville Brothers).

The song was also recorded by Bonnie Raitt for her 1975 album Home Plate and by Geoff Muldaur (1976), Lowell George (1979), Vince Gill (1993), and Elvis Costello (2005).

The same year, Toussaint collaborated with Paul McCartney and Wings for their hit album Venus and Mars and played on the song "Rock Show".

In 1973, his "Yes We Can Can" was covered by The Pointer Sisters for their self-titled debut album; released as a single, it became both a pop and R&B hit and served as the group's introduction to popular culture.

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.

[44][45] His first television appearance after the hurricane was on the September 7, 2005, episode of the Late Show with David Letterman, sitting in with Paul Shaffer and his CBS Orchestra.

He also performed "Tipitina" in a piano duo with Jon Cleary, and accompanied Irma Thomas on "Old Records", Lloyd Price on "Lawdy Miss Clawdy", and Bonnie Raitt on "What is Success".

[49] The River in Reverse, Toussaint's collaborative album with Elvis Costello, was released on May 29, 2006, in the UK on Verve Records by Universal Classics and Jazz UCJ.

[55] Toussaint performed instrumentals from his album The Bright Mississippi and many of his older songs for a taping of the PBS series Austin City Limits, which aired on January 9, 2015.

[60] His late-blooming career as a performer began when he accepted an offer to play a regular Sunday brunch session at an East Village pub.

Following a concert at the Teatro Lara on Calle Corredera Baja de San Pablo, he had a heart attack at his hotel and was pronounced dead on his arrival at the hospital.

He had been due to perform a sold-out concert at the EFG London Jazz Festival at The Barbican on November 15 with his band and Theo Croker.

[67] In January 2025, the United States Postal Service released a forever stamp honoring Toussaint as part of its Black Heritage series.