In high school, Benjamin (who was then performing as "Andre") met Antwan "Big Boi" Patton. Benjamin and Patton teamed up to form Outkast. Shortly after graduating from high school, the duo was signed to the Atlanta-based LaFace label and released their debut album, Southernplayalisticadillacmuzik, in 1994. Buoyed by the success of the single "Player's Ball", the album went platinum by the end of the year and Outkast was named Best New Rap Group of the Year at the 1995 Source Awards. On their next two albums, ATLiens and Aquemini, Outkast experimented with their sound by adding elements of trip hop, soul, and jungle. The albums were also influenced by a return to traditional black music genres, funk being the prime Example. With Outkast's portrayal of themselves as out-of-place extraterrestrials in ATLiens, "the funkadelic, Futuristic, and seemingly unfamiliar, weird, or eccentric persona projected by André 3000 creates the chance to transcend the more pronounced characterizations of gangstas and pimps so regularly assumed by black men rap artists." Outkast's distinctive southern "player" style is combined with these Afrofuturistic elements to create a new, unique space for their brand of rap within popular culture. Benjamin's lyrics, in particular, took on a more surreal, space-age tinge. Within the time of his second and third albums, Benjamin took up the guitar, painting, and a new relationship with singer Erykah Badu. Outkast's fourth album, Stankonia, introduced Benjamin's new alias André 3000 (largely to distinguish himself from Dr. Dre and his new persona after the end of his relationship) and increased the group's crossover appeal with the single "Ms. Jackson", which hit number one on the Billboard Hot 100. The song was written in the aftermath of Benjamin's breakup with Badu and was a fictionalized account of the disintegration of their relationship. In 2002, Outkast released a greatest hits album, Big Boi and Dre Present... OutKast which contained three new tracks. One track, "The Whole World", won a Grammy for Best Rap Performance by a Duo or Group. Later that year, Benjamin participated in the Dungeon Family group album, which saw a number of prominent Atlanta-based hip-hop groups combine into a supergroup. In 2002, André 3000 was referenced on the song "Till I Collapse" by Eminem, who considered him one of the best Rappers ever.

In 2004, alongside Alicia Silverstone, Benjamin was voted by People for the Ethical Treatment of Animals (PETA) to be the 'World's Sexiest Vegetarian Celebrity'. He is a childhood friend of Fonzworth Bentley. Benjamin also has a son named Seven Sirius Benjamin (born November 18, 1997) with R&B singer Erykah Badu. Benjamin was arrested in Henry County, Georgia in March 2009 after being caught driving his 2007 Porsche Carrera 109 mph in a 65 mph speed zone.

In 2003, Outkast released Speakerboxxx/The Love Below, a double album which highlighted the differences in the musical styles of the group's two members. Benjamin's half of the album, The Love Below, garnered the most attention from mainstream audiences, with the popular singles "Hey Ya!" and "Roses". The album's fourth single and video (Benjamin's third), "Prototype", was released shortly after. Big Boi's Speakerboxxx spawned the top ten hit "The Way You Move" and the relatively successful "Ghetto Musick". The Love Below was, unlike Speakerboxxx, an exercise in funk, jazz, and alternative music, featuring sung vocals from Benjamin (instead of rapped). Rolling Stone compared Benjamin to an indie-rock Little Richard" on Outkast's 2003 Number 1 international hit 'Hey Ya!" and later declared the hit one of The 500 Greatest Songs of All Time, In 2006, Outkast released their sixth album as a group, Idlewild. The album served as a Soundtrack to the group's musical film Idlewild. The film centered on life in a 1930s setting and the album took influences from music of that era, particularly blues. Benjamin had a few rapped verses on the album, including on the first single "Mighty O", but mostly stuck with singing as he had on The Love Below. The album actually postponed the release of the theatrical Idlewild, as Andre 3000 and Big Boi were concentrated more on the production of the music than the movie. In an odd turn of events, the movie was finished before the album was, and because of that, the movie was postponed about a year. This was because the crew of Outkast and its associates' had developed the idea of creating a movie before the release of one of their early albums, Aquemini. Thus, when it finally came time to collaborate as a group on the movie, they had most of the details worked out, including a script, as stated by Andre 3000 himself in an interview he had conducted with Billboard in 2006.

Benjamin has made appearances in Families, The Shield (he plays Robert Huggins, a character that originated in an episode titled "On Tilt" from Season 3 in 2004), Be Cool, Revolver, Semi Pro, and Four Brothers. He was also cast as Percival in Idlewild, released on August 26, 2006. He voiced a crow in Charlotte's Web, a movie adaptation of the 1952 children's book. As of November 2006, he voiced "Sunny Bridges," a prize-winning musician who gives up touring to teach at his alma mater, in Class of 3000, an animated series he produced on Cartoon Network. Benjamin was accused by Timothy Mcgee for supposedly 'stealing' his idea of the show. He has also worked with Esthero on a promotional version of "Jungle Book" which was on a Wikked lil' grrrls sampler, but never made it to the actual album due to issues with Esthero's label, Warner Bros.. The following year, he appeared in the basketball comedy Semi-Pro, with Woody Harrelson and Will Ferrell. He also starred in the 2007 film Battle in Seattle, a film about the 1999 Seattle World Trade Organization protests. Benjamin was a member of Quentin Tarantino and Lawrence Bender's production company A Band Apart until its close in 2006; he then formed his own company, Moxie Turtle. In May 2012, Benjamin began filming a biographical film about Jimi Hendrix entitled All Is By My Side. It premiered at the 2013 Toronto International Film Festival on September 7, 2013. His performance was met with critical acclaim and earned him a nomination for the Independent Spirit Award for Best Male Lead. In 2016, Benjamin had a recurring role as Michael LaCroix on the second season of the anthology crime drama series American Crime.

Benjamin posed for a print advertising campaign by Declare Yourself, a campaign encouraging voter registration among youth for the 2008 United States presidential election. In the ads by Photographer David LaChapelle, he has his mouth gagged by a bow-tie in a symbolic function.

On June 24, 2011, Beyoncé's fourth studio album entitled 4 was released. Benjamin featured on the track "Party", his first collaboration with the singer. The song was later nominated for the Award for Best Rap/Sung Collaboration at the Grammy Awards held in 2012. Benjamin continued his string of guest appearances throughout the year – featuring on Lloyd's song "Dedication to My Ex (Miss That)", Lil Wayne's "Interlude" and Drake's "The Real Her". He also featured on the track "Play the Guitar" by B.o.B.

On July 10, 2012, Channel Orange, the debut album by singer-songwriter and Odd Future member Frank Ocean, was released. Benjamin was featured on the song "Pink Matter," supplying vocals and guitar. Later, on July 30, 2012, Rick Ross's album God Forgives, I Don't was released, featuring Benjamin on the song "Sixteen", once again supplying vocals and guitar. Later in the year, Benjamin also featured on T.I.'s album Trouble Man: Heavy Is the Head on the song "Sorry". T.I. noted that the collaboration was a "proud moment" for him.

After being seen in the studio with Producer Mike WiLL Made It, it was reported on August 3, 2013, that Andre 3000 would be releasing a new solo album in early 2014. However, the following day a representative for Benjamin told Billboard that "there is no official confirmation on that report." In 2014, Benjamin appeared on fellow Dungeon Family member Future's second studio album, Honest, on a song titled "Benz Friendz (Whatchutola)".

Benjamin was a vegan for fifteen years. By 2014, he had given it up stating:

In November 2015, Benjamin made a surprise guest appearance on the track "Hello" from Erykah Badu's mixtape But You Caint Use My Phone.

In 2016, Benjamin presented background vocals on the track "30 Hours" by Kanye West off his album The Life of Pablo. Earlier that year, Benjamin revealed that he was in the process of recording new music. He also appeared on the song "Solo (Reprise)" by Frank Ocean off his album Blonde. In the song, Andre is disappointed with the direction that hip-hop has taken since he first entered the rap game over 20 years ago. Benjamin also appeared on the track, "the ends" on Travis Scott's second studio album, Birds in the Trap Sing McKnight. Also in 2016, he appears on the song "Kids..." By A Tribe Called Quest from the album We Got It from Here... Thank You 4 Your Service. He was also featured on two tracks on Kid Cudi's 2016 album, Passion, Pain & Demon Slayin'.