Born in New York City, Talbot started his musical career singing on street corners at the age of 14. He moved to New Jersey with his family the next year, and by 17 he had moved to Los Angeles. There, he befriended Ralph Molina, Danny Whitten and Benjamin Rocco. Together they formed a Doo-wop group called Danny and the Memories. After moving the group to San Francisco, they morphed into The Psyrcle, which eventually grew to encompass Leon and George Whitsell along with Bobby Notkoff. At this point, Talbot and his bandmates renamed the group The Rockets.
In 1967, the group met Neil Young, who at the time was a member of Buffalo Springfield. This meeting saw Molina, Whitten, and Talbot join forces with Young to create Crazy Horse.
Talbot began performing solo in 1999 at small venues, supported by fans of Crazy Horse. In October 2004, Talbot struck out on his own with The Billy Talbot Band, releasing the album Alive in the Spirit World on Sanctuary Records.