Vestine's love of music and the blues in particular was fostered at an early age when he accompanied his father on canvasses of black neighborhoods for old recordings . Like his father, Henry became an avid collector, eventually coming to own tens of thousands of recordings of blues, hillbilly, country, and Cajun music. At Henry’s urging, his father also used to take him to blues shows at which he and Henry were often the only white people present. Later Henry was instrumental in the "rediscovery" of Skip James and other Delta musicians.
In the mid-1950s, Henry and his childhood friend from Takoma Park, John Fahey began to learn how to play guitar and sang a mixed bag of pop, hillbilly, and country music, particularly Hank Williams. Soon after the family moved to California, Henry Vestine joined his first junior high band Hial King and the Newports. On his first acid trip with a close musician friend, he went to an East LA tattoo parlor and got the first of what was to be numerous tattoos: the words "Living The Blues". Later, in 1969, that became the title of a double album by Canned Heat. By the time he was seventeen he was a regular on the Los Angeles club circuit. He became a familiar sight at many black clubs, where he often brought musician friends to turn them on to the blues. Henry became friends with Cajun guitarist Jerry McGhee. It was from him that Henry learned the flat pick and 3-fingerstyle that was to become so much a part of Henry’s own style. He was an early fan of Roy Buchanan and his favorite guitar players included T-Bone Walker, Johnny "Guitar" Watson, Sonny Sharrock ,Freddie King , and Albert Collins. In Canned Heat he was able to play and record with John Lee Hooker whom he had admired since the late 1950s.
His friend Fahey was to be instrumental in the formation of Canned Heat. He had introduced Al Wilson, whom he knew from Boston, to Henry and Bob and Richard Hite. Wilson, Vestine and the Hite brothers formed a jug band that rehearsed at Don Brown’s Jazz Man record Shop. Bob Hite and Alan Wilson started Canned Heat with Kenny Edwards as a second guitarist, but Henry was asked to join. The first notable appearance of the band was the following year when they played at the Monterey Pop Festival. Shortly after Canned Heat’s first album was released, Henry burst into musical prominence as a guitarist who stretched the idiom of the blues with long solos that moved beyond the conventional genres. He had his own style and a trademark piercing treble guitar sound. Vestine missed playing at the Woodstock Festival in 1969, having quit the band the previous week. In 1995, he explained to an Australian reporter that "[a]t the time, it was just another gig. It was too bad I wasn’t there, but I just couldn’t continue with the band at the time." There had some tension between him and bassist Larry Taylor. When Taylor quit Canned Heat, Vestine returned; their alternating membership in the band was to be repeated a few more times over the years.
While Canned Heat played at Woodstock in August 1969, Henry was invited to New York City for session work with avant-garde jazz great Albert Ayler . That session work resulted in two releases on the Impulse label.
At the same time he developed an intense interest in Harley Davidson motorcycles. He eventually owned eleven of them. Prior to his death he was looking forward to playing at their 75th Anniversary Celebration. Over the years he had also a close relationship with the Hells Angels.
Terry Robb brought Vestine to Portland and they did some recording together. Henry began playing with the Pete Carnes Blues Band and made his way to Eugene when the band folded in the mid 1980s. He played the regional club scene with a number of blues and blues-rock groups including James T. and The Tough. From that band he was to bring James Thornbury to a reconstituted Canned Heat.
Vestine toured with Canned Heat in Australia and Europe, where the band had a popularity that far surpassed the recognition they got in the United States. When he returned to Eugene he would play with The Vipers, a group of veteran Eugene blues musicians who perform throughout the Northwest. He continued to record including sessions with Oregon bands such as Skip Jones and The Rent Party Band , Terry Robb, and The Vipers. He also recorded the album Guitar Gangster with Evan Johns in Austin.
Henry Vestines's ashes are interred at the Oak Hill Cemetery outside of Eugene, Oregon. A memorial fund has been set up in his name. The fund will be used for maintenance of his resting place at Oak Hill Cemetery and, when it is possible, for conveyance of some of his ashes to the Vestine Crater on the moon, as has been his wish.