Clark was born in Monahans, Texas, and eventually settled in Nashville, where he helped create the progressive country and outlaw country genres. His songs "L.A. Freeway" and "Desperados Waiting for a Train" that helped launch his career were covered by numerous performers. The New York Times described him as "a king of the Texas troubadours", declaring his body of work "was as indelible as that of anyone working in the Americana idiom in the last decades of the 20th century".
He was an accomplished luthier and often played his own guitars. He achieved success as a songwriter with Jerry Jeff Walker's recordings of "L.A. Freeway" and "Desperados Waiting for a Train". Artists such as Johnny Cash, David Allan Coe, Vince Gill, Ricky Skaggs, Steve Wariner, Hayes Carll, Brad Paisley, John Denver, Alan Jackson, Rodney Crowell, The Highwaymen, and Kenny Chesney have recorded Clark's songs. Emmylou Harris has accompanied him on several recordings, particularly his own version of "Desperados Waiting for a Train" on his first album, Old No. 1, released in 1975.
Numerous artists have charted with Clark-penned tunes. In 1982, Bobby Bare made it to the Country Top Twenty with Clark's "New Cut Road". That same year, bluegrass leader Ricky Skaggs hit No. 1 with Clark's "Heartbroke", a song that permanently established his reputation as an ingenious songwriter. Among the many others who have covered Clark's songs are Vince Gill, who took "Oklahoma Borderline" to the Top Ten in 1985; The Highwaymen, who introduced "Desperados Waiting for a Train" to a new generation that same year; and John Conlee, whose interpretation of "The Carpenter" rode into the Top Ten in 1987. Clark is frequently referred to as The Fifth Highwayman.
Steve Wariner took his cover of Clark's "Baby I'm Yours" to No. 1 in 1988; Asleep at the Wheel charted with Clark's "Blowin' Like a Bandit" the same year. Crowell was Clark's co-writer on "She's Crazy for Leavin'", which in 1989 became the third of five straight #l hits for Crowell. Brad Paisley and Alan Jackson cover Clark's "Out in the Parkin' Lot," co-written with Darrell Scott, on Paisley's Time Well Wasted CD. Jimmy Buffett obviously influenced by Jerry Jeff Walker's earlier quality cover of "Boats to Build" on 1997's "Cowboy Boots & Bathin Suits", then covered Clark's "Boats to Build" and "Cinco de Mayo in Memphis". Clark credits Townes Van Zandt as being a major influence on his songwriting. They were best friends for many years until Van Zandt's death in 1997, and since then Clark has included one of Van Zandt's compositions on most of his albums. In 1995, he recorded a live album with Van Zandt and Steve Earle, Together at the Bluebird Cafe, which was released in October 2001. Other live material can be found on his album Keepers.
In May 2008, Clark canceled four concerts after breaking his leg. After two months on crutches, he began to perform again on July 4 at the Smithsonian Folklife Festival in Washington, DC, where he appeared with Verlon Thompson. On June 20, 2009, Clark announced a new album entitled "Somedays the Song Writes You" which was released on September 22, 2009. It features originals along with a Townes Van Zandt song entitled "If I Needed You".
In December 2011, This One's For Him: A Tribute to Guy Clark (a two-CD set) was released by Icehouse Music. The CD won Americana Album of the Year
Guy Clark won the Grammy Award for Best Folk Album in 2014 for My Favorite Picture of You.
On May 13, 2016, rock supergroup Hard Working Americans released the album "Rest in Chaos," which features a cover of Clark's "The High Price of Inspiration." Clark played on the recording.
On May 17, 2016, Clark died in Nashville following a lengthy illness and according to one obituary, he died of cancer.