Domino was born on February 26 in New Orleans, Louisiana. He first attracted national attention with "The Fat Man" in 1949 on Imperial Records. This song has been credited by some as being the first rock and roll record, featuring a rolling piano and Domino doing "wah-wah" vocalizing over a fat back beat. The record, a re-working of "Junker's Blues" by Champion Jack Dupree, was a massive hit, selling over a million copies and peaking at #2 on the Billboard R&B charts. It has been estimated that Domino has sold in excess of 110 million records.

Domino then released a series of hit songs with producer and co-writer Dave Bartholomew, saxophonists Herbert Hardesty and Alvin "Red" Tyler and drummer Earl Palmer. Other notable and long-standing musicians in Domino's band were saxophonists Reggie Houston, Lee Allen, and Fred Kemp, who was also Domino's trusted bandleader. Domino finally crossed into the pop mainstream with "Ain't That a Shame" (1955), which hit the Top Ten, though Pat Boone characteristically hit #1 with a milder cover of the song that received wider radio airplay in a racially segregated era. Domino would eventually release 37 Top 40 singles, including "Whole Lotta Loving" and "Blue Monday.

His 1956 up-tempo version of the 1940 Vincent Rose, Al Lewis & Larry Stock song, "Blueberry Hill" reached #2 in the Top 40, was #1 on the R&B charts for 11 weeks, and was his biggest hit. Blueberry Hill sold more than 5 million copies worldwide in 1956-57. The song had earlier been recorded by Gene Autry, and Louis Armstrong among many others.

Fats appeared in two films released in 1956: Shake, Rattle & Rock! and The Girl Can't Help It. On December 18, 1957, Domino's hit, "The Big Beat," was featured on Dick Clark's American Bandstand. Domino was a huge star in Jamaica and can be considered a father of reggae music along with Louis Jordan. The well known "upbeat" style of guitar in reggae can be directly traced to his piano playing.

Domino continued to have a steady series of hits for Imperial through early 1962, including the 1960 "Walkin' to New Orleans," written by Bobby Charles. Twenty-two of his Imperial singles were double-sided hits -- that is, both the A-side and the B-side of the single charted (i.e., 44 songs). After he moved to ABC-Paramount Records in 1963, however, Domino's chart career was drastically curtailed. He had a hit with 1963's "Red Sails In The Sunset," but by the end of 1964, the British Invasion had changed the tastes of the record-buying public, and Domino's chart run was over.

Despite the lack of chart success, Domino continued to record steadily until about 1970, and sporadically after that. He also continued as a popular live act for several decades. He was furthermore acknowledged as an important influence on the music of the 1960s and 1970s by some of the top artists of that era; Paul McCartney reportedly wrote the Beatles song, "Lady Madonna," in an emulation of Domino's style.

Domino did manage to return to the "Hot 100" charts one last time in 1968. Ironically, it was with a cover of The Beatles' "Lady Madonna," which appeared at exactly #100 for two consecutive weeks.

In the 1980s, Domino decided he would no longer leave New Orleans, having a comfortable income from royalties and a dislike for touring, and claiming he could not get any food that he liked anyplace else. His induction into the Rock and Roll Hall of Fame and an invitation to perform at the White House failed to persuade Domino to make an exception to this policy. He lived in a mansion in a predominantly working-class Lower 9th Ward neighborhood, where he was a familiar sight in his bright pink Cadillac. He makes yearly appearances at the New Orleans Jazz and Heritage Festival and other local events. Domino was awarded the Grammy Lifetime Achievement Award in 1987. In 2004, Rolling Stone Magazine ranked him #25 on their list of the 100 Greatest Artists of All Time.

When Hurricane Katrina was approaching New Orleans in August 2005, Domino chose to stay at home with his family, due to his wife's poor health. His house was in an area that was heavily flooded. He was thought to be dead, with someone spray-painting a message on his home, "RIP Fats. You will be missed." This was shown in news photos. On September 1, Domino's agent, Al Embry, announced that he had not heard from the musician since before the hurricane had struck.

Later that day, CNN reported that Domino was rescued by a United States Coast Guard helicopter. His daughter, gospel singer Karen Domino White, identified him from a photo shown on CNN. The Domino family was then taken to a Baton Rouge shelter, after which they were picked up by JaMarcus Russell, the starting quarterback of the Louisiana State University football team, and Fats' granddaughter's boyfriend. He let the Dominos stay in his apartment. The Washington Post reported that on Friday, September 2, the Dominos had left Russell's apartment, after sleeping three nights on the couch. "We've lost everything," Domino said, according to the Post story.

By January 2006, work to gut and repair Domino's home and office had begun.

Domino was the first artist to be announced as scheduled to perform at the 2006 Jazz & Heritage Festival, although he was too ill to perform and was only able to offer the audience an on-stage greeting. Domino also released an album Alive and Kickin' in early 2006 to benefit the Tipitina's Foundation, which supports indigent local musicians. The title song was recorded after Katrina, but most of the cuts were from unreleased sessions in the 1990s.

On January 12, 2007 Fat Domino was honored with OffBeat Magazine's Lifetime Achievement Award at the annual Best of the Beat Awards held at House of Blues in New Orleans. Mayor C. Ray Nagin declared the day "Fats Domino Day in New Orleans" and presented Fats Domino with a signed declaration. OffBeat publisher Jan Ramsey and WWL-TV's Eric Paulsen presented Fats Domino with the Lifetime Achievement Award. An all-star musical tribute followed with an introduction by the legendary producer Cosimo Matassa. The Lil' Band O' Gold rhythm section, Warren Storm, Kenny Bill Stinson, David Egan and C.C. Adcock, not only anchored the band, but each contributed lead vocals, swamp pop legend Warren Storm leading off with "Let the Four Winds Blow" and "The Prisoner Song," which he proudly introduced by saying, "Fats Domino recorded this in 1958.. and so did I." The horn section included Lil' Band O' Gold's Dickie Landry, the Iguanas' Derek Huston, and long-time Domino horn men Roger Lewis, Elliot "Stackman" Callier and Herb Hardesty. They were joined by Jon Cleary (who also played guitar in the rhythm section), Al "Carnival Time" Johnson, Irma Thomas, George Porter, Jr. (who, naturally, came up with a funky arrangement for "You Keep On Knocking"), Art Neville, Dr. John and Allen Toussaint, who wrote and debuted a song in tribute of Domino for the occasion. Though Domino didn't perform, those near him recall him playing air piano and singing along to his own songs.

Fats Domino returned to stage on May 19th, 2007 at Tipitina's at New Orleans, performing to a full house. A foundation has been formed and a show is being planned for Domino and the restoration of his home, where he intends to return someday. "I like it down there" he said in a February, 2006 CBS News interview.

In September of 2007, The Louisiana Music Hall Of Fame honored "Fats" Domino for his contributions to Louisiana music by inducting him into The Louisiana Music Hall Of Fame.