Floyd recorded a few solo sides for Lupine, and moved to Washington, D.C., for a time to work with his DJ friend, Al Bell; the two founded a label and production company, Safice, co-writing songs and releasing Floyd's recordings. When Bell accepted a job as promotions director at Stax, Floyd followed him to Memphis, where he signed on with Stax as a staff writer and producer. He worked chiefly with Carla Thomas and William Bell at first, and often wrote in tandem with house guitarist Steve Cropper. In early 1966, their composition "634-5789 (Soulsville, USA)" became a number one R&B hit for Wilson Pickett; around the same time, Floyd released his first single for Stax, "Things Get Better," which failed to chart. That summer, Floyd cut "Knock on Wood," another song he'd written with Cropper; initially intended for Otis Redding, the tune wasn't big with Stax management because it was strongly based on the chord changes of Wilson Pickett's "In the Midnight Hour." However, distributor Atlantic smelled a hit, and released the song nationally; their instincts proved correct, as "Knock on Wood" became Stax's third number one R&B hit by the end of the year (strangely, it barely made the Top 30 on the pop charts). Floyd followed his instant soul classic with several more Top 40 R&B hits over the next four years, including "Raise Your Hand," "Love Is a Doggone Good Thing," "On a Saturday Night," "I've Never Found a Girl (To Love Me Like You Do)" (his second biggest hit), and a cover of Sam Cooke's "Bring It on Home to Me."

In spite of diminishing commercial returns, Floyd stayed with Stax as a performer and writer right up to the label's bankruptcy in 1975. He spent two years with the Southern soul/blues label Malaco, recording the album Experience in 1977; while it was regionally popular, the Southern soul sound had long since fallen out of commercial favor. A brief stint at Mercury failed to remake Floyd for the disco age, and after recording with British mod revivalists Secret Affair, he largely drifted away from the studio. Floyd attempted a comeback on Ichiban with 1988's Flashback album; the following year, he performed at President Bush's inaugural ball, and went on to tour with the Blues Brothers Band. In 1998, Floyd made a guest appearance in Blues Brothers 2000, and also performed "634-5789" with Pickett and Jonny Lang. Meanwhile, countless artists have covered "Knock on Wood," most prominently a disco version by Amii Stewart that topped the pop charts in 1979. While in his seventies, Floyd recorded the affirming Eddie Loves You, a project where he revisited some of his classic songs. The album was released in 2008 from a revitalized Stax Records, the perfect pairing of artist and label.