Born in Bridgeport, Connecticut, Mayer grew up in nearby Fairfield, the second of three sons. Soon after getting his guitar, his neighbor gave him a Stevie Ray Vaughan cassette, which began Mayer's intense love of the blues.Despite the reservations of his parents, Mayer became consumed with playing the guitar, and after two years of practice, he started playing at blues bars and other venues in the area, while in high school. In addition to performing alone, he was in a band called Villanova Junction with Joe Beleznay, Tim Procaccini, and Rich Wolf. When Mayer was seventeen, he was stricken with a cardiac arrhythmia that sent him to the hospital for a weekend. The trauma of the incident sparked his songwriting, and he penned his first lyrics the night he got home.

Mayer played the guitar for several years before enrolling in the Berklee College of Music in Boston, Massachusetts at the age of nineteen. After two semesters, he chose to cut his studies short, and at the urging of his college friend and Atlanta native, Clay Cook, the two moved to Atlanta, Georgia. Quickly making a name for their two-man band, LoFi Masters, they began their career in earnest there, frequenting the local coffee house and club circuit in venues like Eddie's Attic. Cook has said, however, that they began to experience musical differences due to Mayer's desire to take the duo in more of a pop direction.The two parted ways and Mayer embarked on a solo career.

After touring in the Aware Festival concerts and having his songs included on Aware compilations, in early 2001, Aware released Mayer's internet-only album entitled Room for Squares. During that time, Aware inked a deal with Columbia Records that gave Columbia first pick in signing Aware artists, and so in September of the same year, Columbia remixed and re-released Room for Squares.In 2005, he began a string of collaborations with various blues artists,In the spring of 2005, Mayer formed the John Mayer Trio with bassist Pino Palladino and drummer Steve Jordan, both of whom he had met through previous studio sessions. The trio played a combination of blues and rock music.