Branch was born at the Great Lakes Naval Hospital in North Chicago, Illinois, United States.

At ten years of age he bought his first harmonica at a Los Angeles Woolworth store.

[1] In August 1969, Branch attended the first Chicago Blues Festival, which was produced by Willie Dixon.

Six years later, after graduating from the University of Illinois, he was touring with the Chicago Blues All-Stars, led by Dixon.

He has recorded with Willie Dixon, Keb Mo, Johnny Winter, Lou Rawls, Koko Taylor, Eddy Clearwater, Honeyboy Edwards, Syl Johnson, Lurrie Bell, Ronnie Baker Brooks, and Taj Mahal.

Likewise, in 2017 the Chicago Blues Fest celebrated the 40th anniversary of Billy Branch and the SOBs.