“Subterranean Homesick Blues” epitomizes Dylan’s purpose in penning the album Bringing It All Back Home; to revitalize the protest rock of the ‘50s. At the time of this song’s creation in the '60s, rock music had become docile. Dylan’s earlier work in the folk genre was an intentional antithesis to the less poignant mainstream rock of the era. Similarly, the song’s syllabic meter was inspired by '50s rock; specifically Chuck Berry’s “Too Much Monkey Business”.

The title for the song refers to a nostalgia for the Beat generation. In 1958, Jack Kerouac wrote The Subterraneans—a semiautobiographical work documenting the lives of urban youth in the Beat generation. For this, the contemporaneous Beat poet Allen Ginsberg referred to the beat poets as “Subterraneans” to highlight the underground nature of their illicit activities. The documentary about Dylan’s 1965 England Tour, Don’t Look Back, opens with the music video for the song where Allen Ginsberg can be seen standing in the background.