Domino first attracted national attention with "The Fat Man" in 1949 on Imperial Records. This song is an early rock and roll record, featuring a rolling piano and Domino doing "wah-wah" vocalizing over a fat back beat. It sold over a million copies and is widely regarded as the first rock and roll record to do so.

Fats 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, "Whole Lotta Loving" and "Blue Monday" among them.

His 1956 up tempo version of the 1940 Bobby Cerdeira, 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. He also hit singles between 1957-1959, including "I'm Walkin'" (Pop #4), "Valley of Tears" (Pop #8), "It's You I Love" (Pop #6), "Whole Lotta Loving" (Pop #6), "I Want to Walk You Home" (Pop #8), and "Be My Guest" (Pop #8).

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 continued to have a steady series of hits for Imperial through early 1962, including "Walkin' to New Orleans" (1960) (Pop #6) co-written by Bobby Charles and "My Girl, Josephine" (Pop #14) from the same year. After Imperial Records was sold to outside interests in early 1963, Domino left the label: "I stuck with them until they sold out", he claimed in 1979.

In all, Domino recorded over 60 singles for the label, placing 40 songs in the top 10 on the R&B charts, and scoring 11 top 10 singles on the pop charts. As well, twenty-two of Domino's Imperial singles were double-sided hits.

Domino moved to ABC-Paramount Records in 1963, where the label dictated that he would record in Nashville rather than New Orleans. As well, he was assigned a new producer (Felton Jarvis) and a new arranger (Bill Justis) - Domino's long-term collaboration with producer/arranger/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. Perhaps as a result of this tinkering with an established formula, Domino's chart career was drastically curtailed.

He released 11 singles for ABC-Paramount, but only had one top 40 entry with "Red Sails In The Sunset" (1963). Then, 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, leaving ABC-Paramount in mid-1965 and recording for a variety of other labels and reuniting with Dave Bartholomew along the way. 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. Ironically, Domino did manage to return to the "Hot 100" charts one final time in 1968 -- with a cover of "Lady Madonna".