Widely cited as one of the most influential songwriters of his generation, Prine was known for his signature blend of humorous lyrics about love, life, and current events, often with elements of social commentary and satire, as well as sweet songs and melancholy ballads.

[3] After serving in West Germany with the U.S. Army, he returned to Chicago in the late 1960s, where he worked as a mailman, writing and singing songs first as a hobby.

Postal Service mailman for five years and was drafted into the United States Army during the Vietnam War, serving as a vehicle mechanic in West Germany before beginning his musical career in Chicago.

In 1970, Chicago Sun-Times film critic Roger Ebert heard Prine by chance at the Fifth Peg and wrote his first printed review, "Singing Mailman Who Delivers A Powerful Message In A Few Words":[12]He appears on stage with such modesty he almost seems to be backing into the spotlight.

[13] He became a central figure in the Chicago folk revival, which also included such singer-songwriters as Steve Goodman, Michael Peter Smith, Bonnie Koloc, Jim Post, Tom Dundee, Anne Hills, and Fred Holstein.

Joined by such established musicians as Jethro Burns and Bob Gibson, Prine performed frequently at a variety of Chicago clubs.

[14] He was offered a one-album deal of covers and with a few of his original songs, by Bob Koester from Delmark Records, but decided the project was not right for him.

[20] His subsequent albums from the 1970s include Sweet Revenge (1973), containing such fan favorites as "Dear Abby", "Grandpa Was a Carpenter", and "Christmas in Prison", and Common Sense (1975), with "Come Back to Us Barbara Lewis Hare Krishna Beauregard".

Bruised Orange (1978) is a Steve Goodman–produced album that gave listeners songs such as "That's The Way That The World Goes 'Round", "Sabu Visits the Twin Cities Alone", "Fish and Whistle", and the title track.

[21] In 1974, singer David Allan Coe achieved considerable success on the country charts with "You Never Even Called Me by My Name", co-written by Prine and Goodman.

[23] Pink Cadillac (1979) features two songs produced by Sun Records founder Sam Phillips, who by this time rarely did any studio work.

The song "Saigon" is about a Vietnam veteran traumatized by the war ("The static in my attic's gettin' ready to blow").

His songs continued to be covered by other artists; the country supergroup The Highwaymen recorded "The 20th Century Is Almost Over", written by Prine and Goodman.

[26] In 1991, Prine released the Grammy-winning The Missing Years, his first collaboration with producer and Heartbreakers bassist Howie Epstein.

[30] On this album is the long track "Lake Marie", a partly spoken word song interweaving tales over decades centered on themes of "goodbye".

All of the tracks are duets with well-known female country vocalists, including Lucinda Williams, Emmylou Harris, Patty Loveless, Dolores Keane, Trisha Yearwood, and Iris DeMent.

[36] In 2005, Prine released his first all-new offering since Lost Dogs and Mixed Blessings, the album Fair & Square, which tended toward a more laid-back, acoustic approach.

[37] On June 22, 2010, Oh Boy Records released a tribute album titled Broken Hearts & Dirty Windows: Songs of John Prine.

The album features members of the modern folk revival, including My Morning Jacket, The Avett Brothers, Conor Oberst and the Mystic Valley Band, Old Crow Medicine Show, Lambchop, Josh Ritter, Drive-By Truckers, Nickel Creek's Sara Watkins, Deer Tick featuring Liz Isenberg, Justin Townes Earle, Those Darlins, and Bon Iver's Justin Vernon.

The exhibit featured a pair of cowboy boots and jacket that Prine often wore on stage, his personal guitar, and the original handwritten lyric to his hit, "Angel From Montgomery".

The American Currents Class of 2016 showcased artists who made a significant impact on country music in 2016, including, Prine.

[42] On February 8, 2018, Prine announced his first new album of original material in 13 years, titled The Tree of Forgiveness, would be released on April 13.

Produced by Dave Cobb, the album was released on Prine's own Oh Boy Records and features guest artists Jason Isbell, Amanda Shires, Dan Auerbach, and Brandi Carlile.

[45] The last song Prine recorded before he died was "I Remember Everything", released on June 12, 2020, alongside a music video.

It was released following the two-hour special tribute show, A Tribute Celebrating John Prine aired on June 11, 2020, which featured Sturgill Simpson, Vince Gill, Jason Isbell, Kacey Musgraves, Bonnie Raitt, Rita Wilson, Eric Church, Brandi Carlile and many other country artists and friends.

After the surgery, a physical therapist put him through an unusual workout to build stamina: Prine was required to run up and down his house stairs, grab his guitar while still out of breath, and sing two songs.

[51] On March 19, 2020, amid the COVID-19 pandemic in the United States, Prine's wife Fiona revealed that she had tested positive for SARS-CoV-2 and had been quarantined in their home apart from him.

[58] In accordance with Prine's lyrical wishes, expressed in his song "Paradise", some of his ashes were spread in Kentucky's Green River.

Then I'll put on something by the writers I've admired and used for years—Rodney Crowell, John Prine, Guy Clark, and the late Steve Goodman are my Big Four ..."[67] Roger Waters, when asked by Word Magazine in 2008 if he heard Pink Floyd's influence in newer British bands such as Radiohead, replied, "I don't really listen to Radiohead.

[69] Prine's influence is seen in the work of younger artists, whom he often mentored, including Jason Isbell, Amanda Shires, Brandi Carlile, Sturgill Simpson, Kacey Musgraves, Margo Price, Tyler Childers, and Robin Pecknold.