[6] When he was a teenager, Memphis experienced the period when rockabilly, western swing, and electric blues were combining to give birth to rock and roll.

This environment was a school for music as well as life for Musselwhite, who eventually acquired the nickname Memphis Charlie.

[8] Musselwhite then took off in search of the rumored "big-paying factory jobs" up the "Hillbilly Highway", Highway 51 to Chicago, where he continued his education on the South Side, making the acquaintance of blues musicians Lew Soloff, Muddy Waters, Junior Wells, Sonny Boy Williamson, Buddy Guy, Howlin' Wolf, Little Walter, and Big Walter Horton.

[6] He spent his time hanging out at the Jazz Record Mart, at the corner of State and Grand, and a nearby bar, Mr. Joe's, with the city's blues musicians, and sitting in with Williams and others in the clubs, playing for tips.

At this time Charters signed him to another contract which led to Musselwhite's first solo outing in 1966, Stand Back!

In time, Musselwhite led his own blues band, and after Elektra Records' success with Paul Butterfield, he released the album Stand Back!

King, Bo Diddley, Eric Clapton, Koko Taylor, Jimmie Vaughan, Dr. John, and Jack DeJohnette.

His 1999 recording, Continental Drifter, is accompanied by Cuarteto Patria, from Cuba's Santiago region, the Cuban music counterpart of the Mississippi Delta.

[6] Because of political differences between Cuba and the United States, the album was recorded in Bergen, Norway, with Musselwhite's wife handling the details.

"[12] His two albums, Sanctuary (which saw a guest appearance by Hooker)[11] and Delta Hardware, were released by Real World Records.

[6] In the latter half of 2011, he went on tour with Cyndi Lauper, having played harmonica on her hit album Memphis Blues.

[21][22] At the 40th Blues Music Awards ceremony in 2019, Musselwhite's joint composition with Ben Harper, "No Mercy In This Land", was named as 'Song of the Year'.

[23] In 2023, Musselwhite won another Blues Music Award with the 'Acoustic Album of the Year' title for his LP, Mississippi Son.

[24] Musselwhite portrays Alvin Reynolds in the 2023 Martin Scorsese film Killers of the Flower Moon.