Born in Kentucky, Stapleton moved to Nashville in 1996 to study for an engineering degree from Vanderbilt University, but dropped out to pursue a career in music.

[3] Stapleton has co-written six number-one singles for other artists on the Hot Country Songs chart[4] including Kenny Chesney's five-week number-one "Never Wanted Nothing More", Josh Turner's "Your Man", George Strait's "Love's Gonna Make It Alright", and Luke Bryan's "Drink a Beer".

[5] He has been credited on albums for artists including Adele, Kelly Clarkson, Brad Paisley, Dierks Bentley, and Taylor Swift.

His debut solo album, Traveller (2015), peaked on top of the US Billboard 200 and received quadruple platinum certification by the Recording Industry Association of America (RIAA).

His third, From A Room: Volume 2 (2017) peaked at number two on the Billboard 200, and his fourth, Starting Over (2020), won his third Grammy for Best Country Album.

He graduated from Johnson Central High School in Paintsville where he played football—opposite future NFL draft #1 pick Tim Couch on three occasions—and was class valedictorian.

He signed with publishing house Sea Gayle Music shortly after moving to Nashville[22] and earned a reputation as a versatile and prolific songwriter.

[34] In 2013, Stapleton and his wife Morgane sang the Waylon Jennings song "Amanda" live at the Grand Ole Opry.

Cure (from the Jompson Brothers), pedal steel player Robby Turner, drummer Derek Mixon, Mickey Raphael on harmonica, and wife Morgane Stapleton singing harmonies.

[46] This performance was considered a career-defining moment by music publications,[47][48] and with his wins that night he was lifted to national prominence.

[56] In 2016, Chris, with Morgane, contributed the track "You Are My Sunshine" to producer Dave Cobb's compilation record project, Southern Family.

Stapleton was the musical guest on the Saturday Night Live episode which aired January 16, 2016, alongside host Adam Driver.

[68] Stapleton was the musical guest on Saturday Night Live for a second time on January 27, 2018, where he performed songs from From A Room: Volume 2 with Sturgill Simpson.

[73] He was Male Vocalist of the Year for the fourth time at the 2021 Country Music Association Awards, and Male Artist of the Year for the third time at the 2022 Academy of Country Music Awards,[74] where he performed "You'll Never Leave Harlan Alive" with Patty Loveless.

[75] Stapleton co-wrote three songs for Justin Timberlake's studio album Man of the Woods (2018), including their collaboration "Say Something", which reached the top ten list on the US Billboard Hot 100 chart.

[76][77] In the same year, Stapleton recorded a cover of "I Want Love" for Restoration: Reimagining the Songs of Elton John and Bernie Taupin.

[78] On April 28, 2019, Stapleton appeared as an extra in "The Long Night", the third episode of the eighth season of the HBO series Game of Thrones.

[79] On August 6, 2019, John Mayer invited Stapleton on stage at his concert to perform a song they had written the day before, titled "I Just Remembered That I Didn't Care".

[82] Over the course of 2019 and 2020, Stapleton recorded and wrote songs with Mike Campbell, formerly the guitarist of Tom Petty and the Heartbreakers.

[86] Stapleton was joined by Cindy Blackman Santana and Snoop Dogg in recording a cover of Phil Collins' "In the Air Tonight" as the 2023 opening theme song for Monday Night Football.

Stapleton's musical influences range from outlaw country and bluegrass to rock and roll and blues.

Los Angeles Times writer Randy Lewis said in 2015 that his singing recalled "the note-bending style of country that traces to Merle Haggard and Lefty Frizzell and the gut-wrenching expressionism of blues and R&B perfected by Ray Charles", while his guitar performances elicited "memories of Texas blues rocker Stevie Ray Vaughan".

[97] Stapleton has cited Charles, Otis Redding, and Freddie King as some of his musical influences,[98][99] along with Kentucky-based country artists, Keith Whitley, Dwight Yoakam and Patty Loveless.