Carlile began learning to play the guitar and write songs at fifteen. At sixteen, she began to perform as a backup singer for an Elvis impersonator.
Before signing to a major record label, performed in local Seattle establishments like The Crocodile, Tractor Tavern, and Paragon with Tim and Phil Hanseroth. Carlile sold her self-released recordings while she busked. Carlile began to attract the attention of the music industry after Dave Matthews heard her band perform at the 2003 Sasquatch! Music Festival.
Columbia Records signed Carlile in late 2004 after hearing her recordings. Her 2005 major label debut, Brandi Carlile included some of those songs as well as newly recorded tracks. After the release of Brandi Carlile, she went on tour with the Hanseroth brothers for almost two years, where they worked on songs that became part of her second Columbia album The Story.
In 2005, she was featured on Rolling Stone's "10 Artists to Watch in 2005" list. By the end of 2006, Carlile had toured as both a warm-up act and as a headliner.
The Story, was released in April 2007. It was produced by T Bone Burnett and includes a collaboration with the Indigo Girls on "Cannonball." The album was recorded in an 11-day long session and tried to capture the sound of her live performances. (The crack in Carlile's vocals during the title track, "The Story," came out by accident and stayed on the record.)
Carlile describes the vocals as "technically wrong but emotionally right." She would also contribute vocals to "Last Tears" from Indigo Girls' Despite Our Differences.
ABC's Grey's Anatomy featured three of her songs: "Tragedy," "What Can I Say," and "Throw it All Away." In April 2007, Grey's Anatomy debuted a version of the video for the single "The Story" interspersed with footage from the show. On 3 May 2007, a special two-hour episode of the show featured Carlile's song "Turpentine" during footage of the Grey's Anatomy spin-off, Private Practice.
In November 2007, Carlile visited England for her first UK gig at the Borderline in London. In February 2008, Carlile performed as special guest to Newton Faulkner on five of his UK tour dates. During March and April 2008 Carlile toured through Australia with Maroon 5 and OneRepublic. In April 2008 she played four dates in the UK and was a guest performer on the BBC2 show, Later... with Jools Holland.
Her third studio album Give Up the Ghost was released on October 6, 2009. The album debuted at #26 on theBillboard 200. The album was produced by Grammy Award winner Rick Rubin and contains a collaboration with Elton John titled "Caroline."
English singer Adele covered The Story's hidden track "Hiding My Heart" on a bonus edition of her 2011 album 21.
Also in 2010, Carlile contributed the track "The Heartache Can Wait" to the Juvenile Diabetes Research Foundation: More Hope For The Holidays album. Proceeds from this album go to benefit the Juvenile Diabetes Research Foundation.
In a November 14, 2002 interview with The Western Front, the official newspaper of Western Washington University, Carlile identified herself as a lesbian.
In an October 17, 2009 interview with the Los Angeles Times, Carlile said; "I hope that somewhere in Small Town, USA, a 15-year-old kid looks to me as a role model the way I looked at the Indigo Girls and Elton John as role models...and I hope they also recognize that the reason why I don't have to have a lot of formality around it, the reason why I don't have to wear it on my sleeve and make a spectacle of it, is because there were people before me who paved the way so I wouldn't have to."