Waller studied classical piano and organ as a child, taught largely by the music director of his Baptist church, who insisted he also learn the organ works of J. S. Bach. As a young adult, Waller apprenticed himself to legendary Harlem stride pianist James P. Johnson. Johnson introduced Waller to the world of rent parties (a party with a piano player, designed to help pay the rent by charging the guests), and soon he developed a performing career.

He was an excellent pianist--now usually considered one of the very best who ever played in the stride style. Many believe that his songwriting and his lovable, roguish stage personality often overshadowed his playing. Before his solo career, he played with many performers, from Erskine Tate to Bessie Smith, but his greatest success came with his own five- or six-piece combo, "Fats Waller and his Rhythm". Fats Waller was such an impressive and talented pianist that he came to the attention of the rich and famous - sometimes whether he wanted to, or not! Fats Waller was in Chicago in 1926 and, upon leaving the building where he was performing, Waller was kidnapped by four men, who bundled him into a car and drove off. The car later pulled up outside the Hawthorne Inn, owned by infamous gangster Al Capone. Fats was ordered inside the building, to find a party in full-swing! With a gun against his back, Waller was pushed towards a piano, whereupon the gangsters demanded he start playing. A terrified Waller suddenly realised he was the 'surprise guest' at Al Capone's birthday party! Soon comforted by the fact that he wouldn't die, Waller played, so it's rumoured, for three whole days! When he left the Hawthorne Inn, he was very drunk, extremely tired, and had earned thousands of dollars in cash, given to him by Capone himself, and by party-goers as tips.

Among his songs are "Squeeze Me" 1919, "Ain't Misbehavin'" 1929, "Blue Turning Grey Over You" 1930, "Honeysuckle Rose" 1929, "I've Got a Feeling I'm Falling" 1929, and "Jitterbug Waltz" 1942.

He collaborated with the Tin Pan Alley lyricist Andy Razaf and had a commercially successful career, which according to some music critics eclipsed his great musical talent. His nickname came about because he weighed nearly 300 pounds (136 kg). His weight and drinking are believed to have contributed to his death.

Waller also made a successful tour of the British Isles in the late 1930's, and appeared in one of the earliest BBC Television broadcasts. He also appeared in several feature films and short subject films, most notably "Stormy Weather" in 1943.

With Razaf he wrote "What Did I Do (To Be So Black and Blue)?" 1929 which became a hit for Louis Armstrong. This song, a searing treatment of racism, black and white, calls into question the accusations of "shallow entertainment" levelled at both Armstrong and Waller.

On December 15, 1943, at age 39, Waller died of pneumonia aboard an eastbound train in the vicinity of Kansas City, Missouri, following a west coast engagement.

Though Waller could read and write music well (from his classical keyboard studies as a child) and would even, on occasion, perform organ works of Bach for small groups, his brilliant improvisations have had to be transcribed from old recordings and radio broadcasts. The pianist and keyboard professor Paul Posnak has recently produced transcriptions of 16 of Waller's greatest solos, published by Hal Leonard, and himself performs these in concerts worldwide.