Mothersbaugh attended Kent State University as an art student, where he met Devo co-founders Gerald Casale and Bob Lewis. In early 1970, Lewis and Casale formed the idea of the "devolution" of the human race after Casale's friends Jeffrey Miller and Allison Krause were killed by Ohio National Guardsmen on university grounds during what came to be known as the Kent State shootings. Intrigued by the concept, Mothersbaugh joined them, building upon it with elements of early post-structuralist ideas and oddball arcana, most notably unearthing the infamous Jocko-Homo Heavenbound pamphlet (the basis for the song "Jocko Homo"). This association culminated in 1973, when the trio started to play music as Devo. Following the commercial failure of their sixth studio album Shout, Warner Bros. dropped Devo. Shortly after, claiming to feel creatively unfulfilled, drummer Alan Myers left the band, causing the remaining band members to abandon the plans for a Shout video LP, as well as a tour.
In 1987, Devo reformed with new drummer David Kendrick, formerly of Sparks, to replace Myers. Their first project was a soundtrack for the flop horror film Slaughterhouse Rock, starring Toni Basil and they released the albums Total Devo (1988) and Smooth Noodle Maps (1990), on Enigma.
Devo had a falling-out and played two shows in 1991 before breaking up. Around this time, members of Devo appeared in the film The Spirit of '76, except for Bob Mothersbaugh. In 1989, Mark Mothersbaugh established Mutato Muzika, a commercial music production studio, hiring Ryan Moore and Bob Casale; Bob Mothersbaugh was also involved.
2006, Devo worked with Disney on the Devo 2.0 project: a band of child performers was assembled to re-record Devo songs. The Akron Beacon Journal wrote, "Devo recently finished a new project in cahoots with Disney called Devo 2.0, which features the band playing old songs and two new ones with vocals provided by children. Their debut album, a two disc CD/DVD combo entitled DEV2.0, was released on March 14, 2006. The lyrics of some of the songs were changed for family-friendly airplay, which has been claimed by the band to be a play on irony of the messages of their classic hits. Mothersbaugh doesn't rule out the idea of the band gathering in the studio, eventually, to record a new Devo album." The album, Something for Everybody was eventually released in June 2010, preceded by a 12" single of "Fresh"/"What We Do".
Devo was awarded the first Moog Innovator Award on October 29, 2010, during Moogfest 2010 in Asheville, North Carolina. The award aims to celebrate "pioneering artists whose genre-defying work exemplifies the bold, innovative spirit of Bob Moog". Devo was scheduled to perform at Moogfest, but canceled three days beforehand after Mark's brother Bob Mothersbaugh (lead guitar) injured his hand. He and Gerald Casale collaborated with Austin, Texas, band The Octopus Project to perform "Girl U Want" and "Beautiful World" at the event instead.