He came to prominence in 2004 when he released The Grey Album, which combined vocal performances from Jay-Z's The Black Album with instrumentals from The Beatles' The Beatles (aka the White Album).

He formed Gnarls Barkley with CeeLo Green and produced its albums St. Elsewhere and The Odd Couple. In 2009 he collaborated with James Mercer of the indie rock band The Shins to form the band Broken Bells. In addition, Burton worked with rapper MF Doom as Danger Doom and released the album The Mouse and the Mask.

As a producer Danger Mouse produced the second Gorillaz album, 2005's Demon Days, as well as Beck's 2008 record Modern Guilt and three albums with The Black Keys (Attack & Release, El Camino and Turn Blue). In 2016, Danger Mouse produced, performed on and co-wrote songs for the eleventh studio album by the Red Hot Chili Peppers titled The Getaway. Danger Mouse has also produced and co-written albums by Norah Jones (Little Broken Hearts), Electric Guest (Mondo), Portugal. The Man (Evil Friends), Adele (25), and ASAP Rocky's (At.Long.Last.ASAP (ALLA)). He has been nominated for 18 Grammy Awards and has won 5. He's been nominated in the Producer of the Year category five times, and won the award in 2011.

Danger Mouse was listed as one of Esquire magazine's 75 most influential people of the 21st century.