Born in Stockton, California, Phillips began playing the guitar in his early teens. At age 19, he moved to Los Angeles where he worked tarring roofs to fund evening classes at UCLA and forming bands. He eventually dropped out of college and linked up with an old friend from Stockton named Jeffery Clark. In the late 1980s, Phillips lived on campus at CalArts with Future wife Denise Siegel, whom he met at a party through a fellow student and first Shiva Burlesque Bassist, James Brenner. Phillips informally took art classes, went to public lectures and film screenings, and immersed himself in the school's World Music program until 1990. Shiva Burlesque released two LPs, Shiva Burlesque (Nate Starkman & Son; 1987) and Mercury Blues (Fundamental; 1990). Brenner was replaced by Paul Kimble, thus completing what would be the basis of Grant-Lee Buffalo. But Shiva Burlesque made no commercial impact, and Phillips and Clark disbanded in 1990. Phillips began playing solo around Los Angeles under the stage name Grant-Lee Buffalo.

Following those handful of solo shows at clubs around Hollywood, Phillips recruited ex-Shiva members Joey Peters (drums) and Paul Kimble (bass) for rehearsals as Grant Lee Buffalo in mid-1991. Phillips was now writing lyrics as well as music, and the trio quickly built up a local following, selling out clubs on the strength of Phillips's intense performance. His political storytelling was delivered in a recently discovered voice: both a soaring falsetto and a drawl that matched his aggressive acoustic guitar stomp and pouting physicality. One song, "Fuzzy", was released on Bob Mould's Singles Only label in 1992 to critical praise and led to Grant Lee Buffalo being signed to Slash Records. The debut LP, also called Fuzzy, was released a year later, upon which Michael Stipe of R.E.M. declared it "the best album of the year hands down". In 1995 Grant-Lee Phillips was named the critics choice for Best Male Vocalist of 1995.

A further three Grant Lee Buffalo albums followed: Mighty Joe Moon (1994), Copperopolis (1996), and Jubilee (1998). A live performance of Mighty Joe Moon's title track is available online from the South by Southwest festival. Though all were heavily promoted through concert touring, they never escaped cult status. Phillips disbanded the band in early 1999.

Phillips signed to the Boston-based indie label Rounder Records and launched a solo career, issuing Ladies' Love Oracle online in 2000. The recording was later more widely released. His first full-length LP, Mobilize, was released in 2001. Being praised as much for its gentleness as Buffalo were for their rock, it featured Phillips on many instruments.

In 2004 Virginia Creeper arrived and with it a more folky, almost country record noted for its complete absence of electric guitar. In 2006 Phillips released another acoustic album, Nineteeneighties. A set of cover versions, it featured songs from The Smiths, Pixies, New Order, Robyn Hitchcock, R.E.M., The Church, and Echo & the Bunnymen. A new record of his own material, Strangelet, was released on March 27, 2007. On October 13, 2009, Grant released "Little Moon" on Yep Roc records. In October 2012, "Walking in the Green Corn" was released, partially funded by fans through a PledgeMusic campaign. Phillips toured with Glen Phillips to support the album.

In 2015, Phillips released The Narrows, which extends Phillips' exploration of roots and folk music.