Neuwirth's introduction to music came while he was studying painting at the Boston Museum School at the end of the 1950s. Neuwirth became part of the Boston academic environment just as the folk-blues revival was coming into swing, and Neuwirth became a friend and fan of such legendary bluesmen as Lightnin' Hopkins, Mississippi John Hurt, Rev. Gary Davis, and Sonny Terry & Brownie McGhee. Neuwirth took up the guitar and began performing his own material on the coffeehouse circuit, first in Cambridge and later in San Francisco during a hitchhiking trip out West. During his days in Cambridge, Neuwirth was introduced to Bob Dylan by Joan Baez, and they became fast friends, as Neuwirth tagged along with the budding "Voice of a Generation" on many of his early tours. Neuwirth unwittingly played a major supporting role in D.A. Pennebaker's documentary Don't Look Back, which followed the increasingly confrontational Dylan during his 1965 U.K. tour, with Neuwirth playing his real-life role as Dylan's trusted sidekick.
Neuwirth also struck up friendships with Kris Kristofferson as the aspiring songwriter was paying his dues in Nashville, and Janis Joplin as she was searching for a new musical direction after leaving Big Brother & the Holding Company. Neuwirth is said to have convinced Joplin to record Kristofferson's "Me and Bobby McGee," as well as co-writing "Mercedes Benz," which like "Bobby McGee" appeared on her posthumously released album, Pearl. Around this time, Neuwirth also befriended Patti Smith, who had recently moved to New York City and, like Neuwirth, was living at the famous bohemians' hangout the Chelsea Hotel; he introduced her to the Big Apple's poet community, and she later wrote a poem for him, "For Bob Neuwirth," which was published in 1971.