Mayer was able to record his first independent album Inside Wants Out with the help of producer Glen Matullo. Mayer and Cook must have parted on good terms, because Cook co-wrote many of the songs on the album including Mayer's most popular hit single, “No Such Thing.” The album was released in 1999, but it wasn't until “launch” label Aware Records saw his talent at the South by Southwest Music Festival in March of 2000, that Mayer's career really began to take off. In 2001, Aware Records released Mayer's internet-only album, Room For Squares. During the time of its release, Aware made a deal with Columbia Records who signed Mayer, and re-released Room For Squares after making some changes. The album was a mixture of most of the songs off of Mayer's first album Inside Wants Out, as well as an added track entitled, “3X5.” This gave Mayer more exposure for the unrecognized talent his first album contained.

Room For Squares made Mayer a star, and by the end of 2002, fans everywhere were in love with his soulful pop style. His hit singles included, “No Such Thing,” “Why Georgia,” and “Your Body Is A Wonderland” (which is the song that won him a Grammy for Best Male Pop Vocal Performance in 2003). Also in 2003, Mayer released a live CD and DVD of a concert he performed at in Birmingham, Alabama. The CD he entitled, Any Given Thursday peaked at number 17 on the Billboard 200 chart, and included his live performance of songs never released before such as “Something's Missing” (which later appeared on his album to come, Heavier Things).

In 2003, Mayer released his next album Heavier Things. Although it did not sell as many copies as Room For Squares, his single off the album, “Daughters” was his most popular yet and even won him a Grammy in 2005 for Song of the Year. Mayer continued touring and recording his live concerts which were released on the music store in iTunes.

However, even with all of his success, Mayer decided to take a turn in a different musical direction in 2004. Although he was popularly known as a soft, acoustic pop singer, Mayer showed the world that he was more than one-dimensional by reinventing his image, not only by partaking in the hip-hop world and working with rappers such as Kayne West and Common, but also by collaborating with blues artists such as Buddy Guy, B.B. King and Eric Clapton. In order to show his versatility, Mayer formed a blues and rock group called the John Mayer Trio in 2005, which included bassist Pino Palladino and drummer Steve Jordan. The Trio opened for the Rolling Stones in October 2005, and in November 2005 released their live album, Try. The first single, “Who Did You Think I Was?,” was a song Mayer wrote to define breaking out of his acoustic pop star persona and becoming more of a true blues artist. The Trio took a break in 2006, while Mayer worked on his album, Continuum. Mayer and Steve Jordan produced the album, and it was released September 12, 2006. Mayer describes the album as a combination of pop and blues music. The most popular song off the album, “Waiting on the World to Change,” earned Mayer another Grammy for Best Pop Song with Vocal in 2007.

Mayer became an icon in the music industry, however, he was still looking to experiment with different genres of music and so he started creating a new sound, which he described as a blend of jazz and pop music. He called this blend “modern music,” and put it to the test when he remixed an acoustic version of his single, “Waiting on the World to Change” with vocals from musician Ben Harper.

Mayer was on the top of the world when he made the cover of Rolling Stone in February of 2007, and was named one of the “New Guitar Gods” of his time. The cover also nicknamed him “Slowhand, Jr.” which is a reference to Eric Clapton and Mayer's amazing guitar skill and talent. Mayer was also selected by TIME magazine as one of the 100 Most Influential People of 2007 .