Along with Big Gipp, T-Mo, and Khujo, Green was an original member of the Atlanta hip hop group Goodie Mob. He is the youngest of the four. The Goodie Mob was a part of the Atlanta rap collective the Dungeon Family, which also included Outkast. Goodie Mob appeared on two tracks on OutKast's 1994 debut album Southernplayalisticadillacmuzik, with Green providing vocals for "Call of da Wild" and "Git Up, Git Out".

During this time, he also contributed backing vocals to TLC's hit 1995 song "Waterfalls".

The group's second album, Still Standing, came out in 1998 and also received much critical praise. Its commercial performance was slightly lower than the group's previous effort, however. Green took more creative control on the group's next album, World Party, which was released in 1999.

Green, along with the rest of the Goodie Mob, had a cameo in the 1999 film Mystery Men, as a member of the Not So Goodie Mob, in which he was credited as "Thomas Burton aka Cee lo". He also has done voice acting work, voicing Prime Cut Miggity-Mo' Macdaddy Gizzabang Doggy Dog Dog on the Brak Show episode "Brakstreet" in 2002, Frank and Buddy Z Class of 3000's Christmas special and as Godzilla in the Robot Chicken episode "Squaw Bury Shortcake" in 2007, and Rev. Rollo Goodlove in the Boondocks episodes "The S-Word" and "The Hunger Strike" in 2008. In 2010, he appeared in T-Pain's Freaknik: The Musical as Light Skin.

Green was married to Christina Johnson, and divorced in 2005. He and Johnson have a son, Kingston, who was born on September 30, 2000, and Green was stepfather to her daughters, Sierra and Kalah. Sierra appeared on the MTV show My Super Sweet 16 for her 16th birthday party.

Green's Arista career was short-lived, as he was dropped after two albums due to low record sales. His first album, Cee-Lo Green and His Perfect Imperfections (2002), was heavily in the vein of various other Dungeon Family releases, with southern soul/funk/jazz backings produced by Green and boasting appearances by fellow Dungeon Fam members Big Gipp and Backbone. The album did not sell very well, but Green achieved some airplay with the single "Closet Freak".

His second Arista album, Cee-Lo Green... Is the Soul Machine (2004) brought a more branched-out sound and more deeply explored southern rap music. This is evidenced by collaborations with "the biggest hip-hop Musicians of all time", including Ludacris, T.I., and Pharrell Williams. The album debuted and peaked at number 2 on the Billboard Top R&B/Hip Hop Album chart. It received critical acclaim and was described as "one of the most ambitious albums to come out of any genre in recent times."

Along with DJ Danger Mouse, Green was part of a duo called Gnarls Barkley. Green first met Danger Mouse at a University of Georgia event. They later collaborated on the remix of the Danger Mouse and Jemini song "What U Sittin' On?" from the album Ghetto Pop Life, before working together again on the 2005 Danger Doom album The Mouse and The Mask on the song "Benzie Box" where Green delivers the chorus.

Gnarls Barkley's first collaborative album, St. Elsewhere, was released on April 24, 2006, in the UK and May 2, 2006, in the United States. St. Elsewhere entered the charts at No.1 in the UK, as did the first single "Crazy". "Crazy" is the first single to reach number one in the UK based on digital download sales alone and is ranked by Rolling Stone as the greatest song of the decade, ergo making it Green's most successful project to date. A second album by Gnarls Barkley, titled The Odd Couple, was released in March 2008. Its first single was released in January called "Run (I'm a Natural Disaster)".

Seeing the success achieved by Gnarls Barkley, Arista and Legacy released a 17-track greatest hits collection of songs by Green, titled Closet Freak: The Best of Cee-Lo Green the Soul Machine. It features predominantly solo tracks by Green and several Goodie Mob songs. His "What Part of Forever" was included in The Twilight Saga: Eclipse Soundtrack. In 2008, he re-did "Kung Fu fighting" for the animated film Kung Fu Panda.

Green recorded and wrote "Language of Love", for the Sex and the City 2 Soundtrack. It was rumoured in mid-2010 that Green was working with Alien Ant Farm on a track slated for appearance on an upcoming album by the latter. This was confirmed the following year, however, the track failed to materialize, with Alien Ant Farm singer Dryden Mitchell stating he planned to do a cover of Easy Lover with Green, but Green never recorded his parts.

On December 31, 2011, Green sang John Lennon's "Imagine" just prior to the ball drop for New Year's Eve at New York City's Times Square. In his rendition, Green replaced the line "and no religion, too" with the words "and all religions true". Many saw this as a substantial revision of the meaning behind Lennon's original lyrics. Shortly after the performance, Green responded via Twitter: "Yo I meant no disrespect by changing the lyric guys! I was trying to say a world where u could believe what u wanted that's all" [sic] Green deleted a series of tweets pertaining to this event shortly thereafter.

On October 30, 2012, Green was accused of sexual battery by a woman with whom he had dined at a Los Angeles restaurant, leading to a nearly year-long investigation by the Los Angeles Police Department. On October 21, 2013, Green pleaded not guilty to a felony charge of furnishing a controlled substance after the Los Angeles District Attorney's Office declined to file a charge of rape of an intoxicated person, citing insufficient evidence. On August 29, 2014, Green pleaded no contest to one felony count of furnishing ecstasy and was sentenced to three years' formal probation, 360 hours of community Service, and ordered to complete 52 Alcoholics Anonymous or Narcotics Anonymous meetings.

On September 10, 2013 Green's appearance on Sirius Radio's The Opie and Anthony Show was cancelled due to the singer's failure to arrive on time. Green was told on arrival that he should leave the studio or he would be escorted from the building.

On August 31, 2014 Green was criticised for tweets relating to his sexual battery court case. Two of his specific tweets regarding rape were "People who have really been raped REMEMBER!!!" and "If someone is passed out they're not even WITH you consciously! so WITH Implies consent". After sending a number of tweets on the topic of rape, he temporarily deactivated his Twitter account. He re-activated it a number of hours later, tweeting the following apology: "I truly and deeply apologize for the comments attributed to me on Twitter. Those comments were idiotic, untrue and not what I believe."

In January 2015, Green released a concept mixtape with music derived from a variety of TV show theme songs, titled TV on the Radio. Green's next studio album, Heart Blanche was released on November 6, 2015. The lead single, "Robin Williams", named after and dedicated to the actor of the same name, was released on July 17, 2015.

In December 2016 Green released a new song and video "F**ck Me I'm Famous" under the alias Gnarly Davidson. Green attended the 59th Grammy Awards in character as Gnarly Davidson, for which he dressed in all gold complete with a face mask. A couple days later Green released a new song and video called "Jay-Z's Girl" The song is a reworking of Rick Springfield's "Jessie's Girl" with lyrics changed to be about his admiration for Jay-Z's wife Beyoncé.

On July 14, 2017, Green performed at the opening ceremony of the 2017 World Aquatics Championships in Budapest.