Against the opposition of his father, a clergyman, Waller became a professional pianist at the age of 15, working in cabarets and theaters.[citation needed] In 1918 he won a talent contest playing Johnson’s “Carolina Shout”, a song he learned from watching a player piano play it. Fats Waller became one of the most popular performers of his era, finding critical and commercial success in the United States and Europe. He was also a prolific songwriter, and many songs he wrote or co-wrote are still popular, such as “Honeysuckle Rose”, “Ain’t Misbehavin'” and “Squeeze Me”. Fellow pianist and composer Oscar Levant dubbed Waller “the black Horowitz”. Waller is believed to have composed many novelty tunes in the 1920s and 1930s and sold them for small sums, attributed to another composer and lyricist. Standards attributed to Fats Waller, sometimes controversially, include “I Can’t Give You Anything but Love, Baby”. Biographer Barry Singer conjectured that this jazz classic was written by Waller and lyricist Andy Razaf and provided a description of the sale given by Waller to the New York Post in 1929—he sold the song for $500 to a white songwriter, ultimately for use in a financially successful show (consistent with Jimmy McHugh’s contributions to Harry Delmar’s Revels, 1927, and then to Blackbirds of 1928). He further supports the conjecture, noting that early handwritten manuscripts in the Dana Library Institute of Jazz Studies of “Spreadin’ Rhythm Around” (Jimmy McHugh ©1935) are in Waller’s hand. Jazz historian P.S. Machlin comments that the Singer conjecture has “considerable [historical] justification”. Waller’s son Maurice wrote in his 1977 biography of his father that Waller had once complained on hearing the song, and came from upstairs to admonish him never to play it in his hearing because he had had to sell it when he needed money. Maurice Waller’s biography similarly notes his father’s objections to hearing “On the Sunny Side of the Street” playing on the radio. Waller recorded “I Can’t Give You…” in 1938, playing the tune but making fun of the lyrics; the recording was with Adelaide Hall who had introduced the song to the world at Les Ambassadeurs Club in New York in 1928.

The anonymous sleeve notes on the 1960 RCA Victor album Handful of Keys state that Fats Waller copyrighted over 400 songs, many of them co-written with his closest collaborator, Andy Razaf. Razaf described his partner as “the soul of melody… a man who made the piano sing… both big in body and in mind… known for his generosity… a bubbling bundle of joy”. Gene Sedric, a clarinetist who played with Waller on some of his 1930s recordings, is quoted in these sleeve notes recalling Waller’s recording technique with considerable admiration: “Fats was the most relaxed man I ever saw in a studio, and so he made everybody else relaxed. After a balance had been taken, we’d just need one take to make a side, unless it was a kind of difficult number.” Fats Waller played with many performers, from Nathaniel Shilkret (on Victor 21298-A) and Gene Austin to Erskine Tate, Fletcher Henderson, McKinney’s Cotton Pickers and Adelaide Hall, but his greatest success came with his own five- or six-piece combo, “Fats Waller and his Rhythm”. On one occasion his playing seemed to have put him at risk of injury. Waller was kidnapped in Chicago leaving a performance in 1926. Four men bundled him into a car and took him to the Hawthorne Inn, owned by Al Capone. Waller was ordered inside the building, and found a party in full swing. Gun to his back, he was pushed towards a piano, and told to play. A terrified Waller realized he was the “surprise guest” at Capone’s birthday party, and took comfort that the gangsters did not intend to kill him. It is rumored that Waller stayed at the Hawthorne Inn for three days and left very drunk, extremely tired, and had earned thousands of dollars in cash from Capone and other party-goers as tips.

In 1926, Fats Waller began his recording association with the Victor Talking Machine Company/RCA Victor, his principal record company for the rest of his life, with the organ solos “St. Louis Blues” and his own composition, “Lenox Avenue Blues”. Although he recorded with various groups, including Morris’s Hot Babes (1927), Fats Waller’s Buddies (1929) (one of the earliest multiracial groups to record), and McKinney’s Cotton Pickers (1929), his most important contribution to the Harlem stride piano tradition was a series of solo recordings of his own compositions: “Handful of Keys”, “Smashing Thirds”, “Numb Fumblin'”, and “Valentine Stomp” (1929). After sessions with Ted Lewis (1931), Jack Teagarden (1931) and Billy Banks’ Rhythmakers (1932), he began in May 1934 the voluminous series of recordings with a small band known as Fats Waller and his Rhythm. This six-piece group usually included Herman Autrey (sometimes replaced by Bill Coleman or John “Bugs” Hamilton), Gene Sedric or Rudy Powell, and Al Casey. Fats Waller wrote “Squeeze Me” (1919), “Keepin’ Out of Mischief Now”, “Ain’t Misbehavin'” (1929), “Blue Turning Grey Over You”, “I’ve Got a Feeling I’m Falling” (1929), “Honeysuckle Rose” (1929) and “Jitterbug Waltz” (1942). He composed stride piano display pieces such as “Handful of Keys”, “Valentine Stomp” and “Viper’s Drag”.

He enjoyed success touring the United Kingdom and Ireland in the 1930s. He appeared in one of the first BBC television broadcasts. While in Britain, Fats Waller also recorded a number of songs for EMI on their Compton Theatre organ located in their Abbey Road Studios in St John’s Wood. He appeared in several feature films and short subject films, most notably Stormy Weather in 1943, which was released July 21, just months before his death. For the hit Broadway show Hot Chocolates, he and Razaf wrote “(What Did I Do to Be So) Black and Blue” (1929), which became a hit for Ethel Waters and Louis Armstrong. Waller performed Bach organ pieces for small groups on occasion. Waller influenced many pre-bebop jazz pianists; Count Basie and Erroll Garner have both reanimated his hit songs. In addition to his playing, Waller was known for his many quips during his performances. Between 1926 and the end of 1927, Waller recorded a series of pipe organ solo records. These represent the first time syncopated jazz compositions were performed on a full-sized church organ. Fats Waller contracted pneumonia and died on a cross-country train trip near Kansas City, Missouri, on December 15, 1943.