Souther was born in Detroit, Michigan, and raised in Amarillo, Texas. As a musician and Songwriter, he was greatly influenced in his formative years by fellow Texan and rock and roll icon Roy Orbison. After moving to Los Angeles County, California, in the late 1960s, Souther met musician and Songwriter Glenn Frey. The two Musicians became roommates and musical collaborators. Souther and Frey formed a folk duo called Longbranch Pennywhistle. Their lone album was released in 1970 on Jimmy Bowen's Amos Records.
Souther married Alexandra Sliwin in March 1969, but divorced in 1972. He dated Linda Ronstadt and Stevie Nicks in the 1970s. Judee Sill's song "Jesus Was a Crossmaker" was written for Souther, who she says broke her heart after a short affair. In December 2002, Souther moved from the Hollywood Hills, California, to Nashville, Tennessee. He remarried in 2004 but divorced Sarah Nicholson from Bansha, Ireland, a second time in 2010.
Souther is probably best known for his songwriting abilities, especially in the field of country rock. He co-wrote some of the biggest hits for the Eagles, including "Best of My Love", "Victim of Love", "Heartache Tonight", and "New Kid in Town". "How Long", which appears on the Eagles' Long Road Out of Eden, was written by Souther and originally recorded on his first solo album in 1972.
He wrote "Run Like a Thief" which appeared on Home Plate by Bonnie Raitt in 1975.
Souther has also contributed as a singer to works written by other artists, including backing vocals with Don Henley on "The Light Is On" for Christopher Cross on his eponymous debut album; on the songs "False Faces" and "Loose Ends" on the late Dan Fogelberg's 1976 LP Nether Lands; and, with Fogelberg, as the Hot Damn Brothers on Fogelberg's 1975 LP Captured Angel.
The Eagles recording, "Heartache Tonight" was released in 1979 and hit Number One on the charts. It was written by Souther, Bob Seger, Glenn Frey and Don Henley.
Souther briefly dated Linda Ronstadt, co-produced her Don't Cry Now album, and wrote songs for several of her multi-platinum albums, including "Faithless Love" from Heart Like a Wheel and "White Rhythm and Blues" on Living in the USA. Souther also recorded several duets with Ronstadt, including "Hasten Down the Wind," "Prisoner in Disguise," "Sometimes You Can't Win", and "Hearts Against the Wind" which was featured in the 1980 film Urban Cowboy.
A collaboration with his old friend James Taylor called "Her Town Too" (from Taylor's platinum-certified Dad Loves His Work album) reached #11 on the Hot 100 and went Top Five on AC radio in 1981.
In 1987, he contributed, performed, and did the vocal arrangements for the Roy Orbison and Friends: A Black and White Night concert and video, sang the Platters' "Smoke Gets In Your Eyes" in Steven Spielberg's 1989 film Always, and wrote the theme song to the 1989-1992 sitcom Anything But Love.
Souther played the character of John Dunaway in the (1989–1990) third season of the television drama Thirtysomething and Ted in the film Postcards from the Edge (1990). He appeared in the audiobook of Jimmy Buffett's A Salty Piece of Land. Souther played Jesse James in the television movie Purgatory in 1999 and Jeffrey Pommeroy in My Girl 2. Souther also appeared in the 2012 mystery thriller Deadline. He had a recurring role in the first season of country music drama series Nashville, which premiered in October 2012 and he reprised his role in a 2017 episode of the fifth season.
Souther co-wrote "Doin' Time For Bein' Young", a song performed by James Intveld for the Soundtrack of the 1990 Johnny Depp movie Cry-Baby.
On October 14, 2008, Souther released If the World Was You, his first new release in 25 years. In the fall of 2009, he released a follow up live album entitled Rain - Live at the Belcourt Theatre, featuring a blend of old and new material.
On May 31, 2011, Souther released Natural History, featuring new versions of his songs recorded by other artists.
On October 9, 2012, he released Midnight in Tokyo, an EP that was recorded live.