At age 14, he was a founding member of the British punk band Sordid Details. He later formed Wonder Stories, a New Romantic group influenced by David Bowie and Roxy Music. Keanan is also lead singer in the band Slinky Vagabond, alongside Glen Matlock of The Sex Pistols, Clem Burke of Blondie, and Earl Slick (guitarist for David Bowie).

Keanan established his eponymous fashion label in 1999. The collection is inspired by subversive subcultures, and mixes high fashion with youth culture, music, and British iconography. Duffty's clothes have attracted a celebrity following that include Mick Jagger, Iggy Pop, David Bowie, Alyssa Milano, Sarah Jessica Parker, and more.

In 2009, Keanan wrote "Rebel Rebel Anti-Style". Tracing the roots of rebel style to the music scene, the book explores how music and "anti-fashion" icons have inspired fashion.