At the age of 14 Adams began learning to play the electric guitar that his mom and stepdad had bought him, and shortly afterwards joined a local band named Blank Label. Adams dropped out of high school in his first week of tenth grade, moving into bandmate Jere McIlwean's rental house just outside Jacksonville. Around this time he performed briefly with two local bands, Ass and The Lazy Stars. Following this, Adams joined The Patty Duke Syndrome and once played in a bar in Jacksonville. After obtaining his GED, Adams left Jacksonville for Raleigh, shortly followed by McIlwean.

Following the break up of The Patty Duke Syndrome, Adams went on to found Whiskeytown with Caitlin Cary, Eric "Skillet" Gilmore, Steve Grothmann and Phil Wandscher. The founding of Whiskeytown saw Adams move to alt-country, describing punk rock as "too hard to sing" in the title track of Whiskeytown's debut album Faithless Street. Whiskeytown was heavily influenced by the country-rock pioneers, most notably Gram Parsons. Whiskeytown quickly gained critical acclaim with the release of their second full-length album, Strangers Almanac, their first major label release.

Adams made his solo debut in 2000, with Heartbreaker. It was met with considerable critical success, but sales were slow. Adams released Gold, the follow up to Heartbreaker, in 2001. It was well received; however, Adams voted against making videos or doing a radio station meet-and-greet type tour for more recording and some live dates. A video was eventually made for album's first single, "New York, New York". The music video featured Adams performing in front of the city's skyline four days before the September 11, 2001 attacks. The video was played often on MTV and VH1 after the attacks and became Adams' breakthrough to mainstream music consumers.

2005 saw Adams join with backing band The Cardinals to produce two albums, Cold Roses and Jacksonville City Nights. Cold Roses, a double album, included backing vocals from Rachael Yamagata on three songs; "Let It Ride", "Cold Roses" and "Friends". His second album of the year, Jacksonville City Nights, featured a duet with Norah Jones on "Dear John". As well as releasing two albums with The Cardinals, Adams released the solo album 29 late in the year. Adams released his ninth album on June 26, 2007, titled Easy Tiger.[10] The album includes many tracks which were debuted during 2006's tours, as well as other older tracks which were previously unreleased. Later that year, Adams revealed that he had endured "an extended period of substance abuse" that ended in 2006. Adams indicated that he routinely snorted heroin mixed with cocaine, and abused alcohol and pills. Adams beat his addiction with the assistance of his girlfriend at the time, Jessica Joffe, using Valium therapy and occasionally attending meetings of Alcoholics Anonymous.

On January 14, 2009, Ryan Adams announced that he was quitting the Cardinals after their final show on March 20, 2009 at the Fox Theatre in Atlanta. Adams cited hearing loss due to Ménière's disease as well as disillusionment with the music industry, the media and audience behavior as reasons for his decision.