He was born in Akron, Ohio.
Mothersbaugh was lead singer of the New Wave rock group Devo. After Devo dissolved in the 1980s, Mothersbaugh went on to a successful career as a writer of music for TV and movies. His credits include the soundtracks for the television show Pee-wee's Playhouse, Rugrats (both the TV series and the movies), MTV's Liquid Television, and many movies including Happy Gilmore, The Big Squeeze, Drop Dead Gorgeous, The Birdcage, Rushmore, and The Royal Tenenbaums. He has also written music for video games, including Crash Bandicoot.
Mothersbaugh also paints, in a style influenced by Surrealism and Andy Warhol.