After living in New York and Florida, Souther moved to Los Angeles in 1969[8] and met musician and songwriter Glenn Frey.

Souther helped the Eagles to form as a backing band for Linda Ronstadt and when they branched out on their own, he played with them at the Troubadour on LA's Sunset Strip.

[9] Souther declined an offer to join The Eagles[10] and instead signed to David Geffen's Asylum label and recorded a debut solo studio album under his own name.

Souther wrote the song "Run Like a Thief" which appeared on Bonnie Raitt's 1975 album, Home Plate.

1976 saw the release of Souther's second solo LP Black Rose, produced by Peter Asher and considered by many to be his finest work.

Souther co-wrote several songs for the Eagles including "Best of My Love", "James Dean", "New Kid In Town", and "Doolin-Dalton".

The Eagles recording "Heartache Tonight", written by Souther, Bob Seger, Frey, and Henley, was released in 1979 and became the band's final chart-topping song on the Billboard Hot 100.

He was an accomplished performer, and Frey commented that the only reason he was not a bigger solo star was that "he gave the Eagles and Linda Ronstadt most of his best songs".

He also 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.

He recorded other duets with Ronstadt, including "Prisoner in Disguise", "Sometimes You Can't Win", and "Hearts Against the Wind", which was featured in the 1980 film Urban Cowboy.

In 1987 he contributed to, performed on, and arranged the vocals for the Roy Orbison and Friends: A Black and White Night concert and video.

He sang the Platters' "Smoke Gets in Your Eyes" in Steven Spielberg's 1989 film Always, and wrote the theme song to the 1989–92 sitcom Anything But Love.