Born in Elmar, Arkansas, Sykes grew up near Helena but at age 15, went on the road playing piano with a barrelhouse style of blues. Like many bluesmen of his time, he travelled around playing to all-male audiences in sawmill, turpentine and levee camps along the Mississippi River, gathering a repertoire of raw, sexually explicit material. His wanderings eventually brought him to St. Louis, Missouri, where he met St. Louis Jimmy Oden.

In 1929 he was spotted by a talent scout and sent to New York to record for Okeh Records.His first release was "'44' Blues" which became a blues standard and his trademark.He quickly began recording for multiple labels under various names including 'Easy Papa Johnson', 'Dobby Bragg' and 'Willie Kelly'. After he and Oden moved to Chicago he found his first period of fame when he signed with Decca Records in 1934. In 1943, he signed with Bluebird Records and recorded with 'The Honeydrippers'.

In Chicago, Sykes began to display an increasing urbanity in his lyric-writing, using an 8-bar blues pop gospel structure instead of the traditional 12-bar blues. However, despite the growing urbanity of his outlook, he gradually became less competitive in the post-World War II music scene. After his RCA Victor contract expired, he continued to record for smaller labels, such as United, until his opportunities ran out in the mid 1950s.

Roosevelt left Chicago in 1954 for New Orleans as electric blues was taking over the Chicago blues clubs. When he returned to recording in the 1960s it was for labels such as Delmark, Bluesville, Storyville and Folkways that were documenting the quickly passing blues history. He lived out his final years in New Orleans, where he died from a heart attackon July 17, 1983.