He attended Howard University, leaving to start work as a helper to an ice delivery man. Domino learned to play the piano in about 1938 from his brother-in-law, the jazz guitarist Harrison Verrett.

By age 14, Domino was performing in New Orleans bars. In 1947, Billy Diamond, a New Orleans bandleader, accepted an invitation to hear the young pianist perform at a backyard barbecue. Domino played well enough that Diamond asked him to join his band, the Solid Senders, at the Hideaway Club in New Orleans, where he would earn $3 a week playing the piano. Diamond nicknamed him “Fats”, because Domino reminded him of the renowned pianists Fats Waller and Fats Pichon, but also because of his large appetite.

Domino was signed to the Imperial Records label in 1949 by owner Lew Chudd, to be paid royalties based on sales instead of a fee for each song. He and producer Dave Bartholomew wrote “The Fat Man”, a toned down version of a song about drug addicts called “Junker Blues”; the record had sold a million copies by 1951. Featuring a rolling piano and Domino vocalizing “wah-wah” over a strong backbeat, “The Fat Man” is widely considered the first rock-and-roll record to achieve this level of sales. In 2015, the song would enter the Grammy Hall of Fame.

While Domino’s own recordings were done for Imperial, he sometimes sat in during that time as a session musician on recordings by other artists for other record labels. Domino’s rolling piano triplets provided the memorable instrumental introduction for Lloyd Price’s first hit, “Lawdy Miss Clawdy”, recorded for Specialty Records on March 13, 1952 at Cosimo Matassa’s J&M Studios in New Orleans (where Domino himself had earlier recorded “The Fat Man” and other songs). Dave Bartholomew was producing Price’s record, which also featured familiar Domino collaborators Hardesty, Fields and Palmer as sidemen, and he asked Domino to play the piano part, replacing the original session pianist.

Domino crossed into the pop mainstream with “Ain’t That a Shame” (mislabeled as “Ain’t It a Shame”) which reached the Top Ten. This was the first of his records to appear on the Billboard pop singles chart (on July 16, 1955), with the debut at number 14. A milder cover version by Pat Boone reached number 1, having received wider radio airplay in an era of racial segregation. In 1955, Domino was said to be earning $10,000 a week while touring, according to a report in the memoir of artist Chuck Berry. Domino eventually had 37 Top 40 singles, but none made it to number 1 on the Pop chart.

Domino’s debut album contained several of his recent hits and earlier blues tracks that had not been released as singles, and was issued on the Imperial label (catalogue number 9009) in November 1955, and was reissued as Rock and Rollin’ with Fats Domino. The reissue reached number 17 on the Billboard Pop Albums chart.

His 1956 recording of “Blueberry Hill”, a 1940 song by Vincent Rose, Al Lewis and Larry Stock (which had previously been recorded by Gene Autry, Louis Armstrong and others), reached number 2 on the Billboard Juke Box chart for two weeks and was number 1 on the R&B chart for 11 weeks. It was his biggest hit, selling more than 5 million copies worldwide in 1956 and 1957. The song was subsequently recorded by Elvis Presley, Little Richard, and Led Zeppelin. Some 32 years later, the song would enter the Grammy Hall of Fame.

On November 2, 1956, a riot broke out at a Domino concert in Fayetteville, North Carolina. The police used tear gas to break up the unruly crowd. Domino jumped out a window to avoid the melee; he and two members of his band were slightly injured. During his career, four major riots occurred at his concerts, “partly because of integration”, according to his biographer Rick Coleman. “But also the fact they had alcohol at these shows. So they were mixing alcohol, plus dancing, plus the races together for the first time in a lot of these places.” In November 1957, Domino appeared on the Ed Sullivan TV program; no disturbance accompanied this performance.

Domino appeared in two films released in 1956: Shake, Rattle & Rock! and The Girl Can’t Help It. On December 18, 1957, his hit recording of “The Big Beat” was featured on Dick Clark’s American Bandstand. He was also featured in a movie of the same name.

Domino was also an important influence on the music of the 1960s and 1970s and was acknowledged as such by some of the top artists of that era. Elvis Presley introduced Fats at one of his Las Vegas concerts, saying, “This gentleman was a huge influence on me when I started out.” Presley also made this comment in a 1957 interview: “A lot of people seem to think I started this business. But rock ‘n’ roll was here a long time before I came along. Nobody can sing that music like colored people. Let’s face it: I can’t sing it like Fats Domino can. I know that.”

Domino had a steady series of hits for Imperial through early 1962, including “Walking’ to New Orleans” (1960, Pop number 6), co-written by Bobby Charles, and “My Girl Josephine” (Pop number 14) in the same year. He toured Europe in 1962 and met the Beatles who would later cite Domino as an inspiration. After returning, he played the first of his many stands in Las Vegas.

Imperial Records was sold in early 1963, and Domino left the label. “I stuck with them until they sold out,” he said in 1979. In all, he recorded over 60 singles for Imperial, placing 40 songs in the top 10 on the R&B chart and 11 in the top 10 on the Pop chart, twenty-seven of which were double-sided hits.

Domino moved to ABC-Paramount Records in 1963. The label dictated that he record in Nashville, Tennessee, rather than New Orleans. He was assigned a new producer (Felton Jarvis) and a new arranger (Bill Justis). Domino’s long-term collaboration with the producer, arranger, and frequent co-writer Dave Bartholomew, who oversaw virtually all of his Imperial hits, was seemingly at an end. Jarvis and Justis changed the Domino sound somewhat, notably by adding the backing of a countrypolitan-style vocal chorus to most of his new recordings. He released 11 singles for ABC-Paramount, several which hit the Top 100 but just once entering the Top 40 (“Red Sails in the Sunset”, 1963). By the end of 1964 the British Invasion had changed the tastes of the record-buying public, and Domino’s chart run was over.

Both John Lennon and Paul McCartney recorded Domino songs. According to some reports, McCartney wrote the Beatles song “Lady Madonna” in emulation of Domino’s style, combining it with a nod to Humphrey Lyttelton’s 1956 hit “Bad Penny Blues”. Domino also recorded the song in 1968. Domino returned to the “Hot 100” chart for the last time in 1968, with his recording of “Lady Madonna”. That recording, as well as covers of two other songs by the Beatles, appeared on his Reprise album Fats Is Back, produced by Richard Perry and with several hits recorded by a band that included the New Orleans pianist James Booker.

Domino appeared in the Monkees’ television special 33⅓ Revolutions per Monkee in 1969. In 1971, he opened for Ike & Tina Turner at Carnegie Hall. He continued to be popular as a performer for several decades. He made a cameo appearance in Clint Eastwood’s movie Any Which Way You Can, filmed in 1979 and released in 1980, singing the country song “Whiskey Heaven”, which later became a minor hit. His life and career were showcased in Joe Lauro’s 2015 documentary The Big Beat: Fats Domino and the Birth of Rock ‘n’ Roll.

Domino was present in the audience of 2,200 people at Elvis Presley’s first concert at the Las Vegas Hilton on July 31, 1969. At a press conference after the show, when a journalist referred to Presley as “The King”, Presley gestured toward Domino, who was taking in the scene. “No,” Presley said, “that’s the real king of rock and roll.” About a photograph made of him and Elvis together, Mr. Domino said: “Elvis told me he flopped the first time he came to Las Vegas. I loved his music. He could sing anything … I’m glad we took this picture.” (Fats Domino (2002). “Music Pioneer Fats Domino Talks About Elvis.” Retrieved from “USA Today.” December 10, 2002.)

John Lennon covered Domino’s composition “Ain’t That a Shame” on his 1975 album “Rock ‘n’ Roll,” his tribute to the musicians who had influenced him.

American band Cheap Trick recorded “Ain’t That a Shame” on their 1978 live album Cheap Trick at Budokan and released it as the second single from the album. It reached 35 of the Billboard Hot 100. Reportedly, this was Domino’s favorite cover. It remains a staple of their live performances, including at their 25th Anniversary concert (which was recorded as the album and DVD Silver) and at their induction into the Rock and Roll Hall of Fame in 2016.

In 1986 Domino was one of the first musicians to be inducted into the Rock and Roll Hall of Fame. He also received the Grammy Lifetime Achievement Award in 1987. Domino’s last album for a major label, Christmas Is a Special Day, was released in 1993.

His last tour was in Europe, for three weeks in 1995. After being ill while on tour, Domino decided he would no longer leave the New Orleans area, having a comfortable income from royalty payments and a dislike of touring and claiming he could not get any food that he liked anywhere else. In the same year, he received the Rhythm & Blues Foundation’s Ray Charles Lifetime Achievement Award.

In 1998, President Bill Clinton awarded him the National Medal of Arts. Domino declined an invitation to perform at the White House.

In 2004, Rolling Stone magazine ranked him number 25 on its list of the “100 Greatest Artists of All Time” in an essay written by Dr. John.

As Hurricane Katrina approached New Orleans in August 2005, Domino chose to stay at home with his family, partly because his wife, Rosemary, was in poor health. His house was in an area that was heavily flooded.

By January 2006, work to gut and repair Domino’s home and office had begun (see Reconstruction of New Orleans). In the meantime, the Domino family resided in Harvey, Louisiana.

In 2006 Domino’s album Alive and Kickin’ was released to benefit the Tipitina’s Foundation, which supports indigent local musicians and helps preserve the New Orleans sound. The album consists of unreleased recordings from the 1990s and received great critical acclaim.

On January 12, 2007, Domino was honored with OffBeat magazine’s Lifetime Achievement Award at the annual Best of the Beat Awards, held at the House of Blues in New Orleans. New Orleans Mayor Ray Nagin declared the day “Fats Domino Day in New Orleans” and presented him with a signed declaration. Domino returned to stage on May 19, 2007, at Tipitina’s at New Orleans, performing to a full house. This was his last public performance. The concert was recorded for a 2008 TV presentation entitled Fats Domino: Walkin’ Back to New Orleans. This was a fund-raising concert, featuring a number of artists. Domino donated his fee to the cause. Later that year, a Vanguard record was released, Goin’ Home: A Tribute to Fats Domino featuring his songs as recorded by Elton John, Neil Young, Tom Petty, Robert Plant, Willie Nelson, Norah Jones, Lenny Kravitz, and Lucinda Williams. A portion of the proceeds was to be used by the Foundation to help restore Domino’s publishing office which had been damaged by the hurricane.

In September 2007, Domino was inducted into the Louisiana Music Hall of Fame.

In 2007, various artists came together for a tribute to Domino, recording a live session containing only his songs. Musicians performing on the album, Goin’ Home: A Tribute to Fats Domino, included Paul McCartney, Norah Jones, Willie Nelson, Neil Young, and Elton John.

The musician was married to Rosemary Domino (née Hall) from 1947 until her death in 2008; the couple had eight children: Antoine III, Anatole, Andre, Antonio, Antoinette, Andrea, Anola, and Adonica. Even after his success he continued to live in his old neighborhood, the Lower Ninth Ward, until after Hurricane Katrina, when he moved to a suburb of New Orleans.

In May 2009, Domino made an unexpected appearance in the audience for the Domino Effect, a concert featuring Little Richard and other artists, aimed at raising funds to help rebuild schools and playgrounds damaged by Hurricane Katrina.

In October 2012, Domino was featured in season three of the television series Treme, playing himself. On August 21, 2016, Domino was inducted into the National Rhythm and Blues Hall of Fame. The ceremony was held in Detroit, Michigan. The other inductees were Dionne Warwick, Cathy Hughes, Smokey Robinson, Prince, and the Supremes. He had received the Rhythm & Blues Foundation’s Ray Charles Lifetime Achievement Award in 1995. His song “The Fat Man” entered the Grammy Hall of Fame in 2015.

Domino died on October 24, 2017, at his home in Harvey, Louisiana, at the age of 89, from natural causes, according to the coroner’s office.

On June 25, 2019, The New York Times Magazine listed Fats Domino among hundreds of artists whose material was reportedly destroyed in the 2008 Universal fire.