Clayton attended West Aurora High School and Columbia College Chicago majoring in illustration. He first published work with the Milwaukee based publisher Fireman Press, home of cult hit The Disposable Assassin, where Ed Clayton took over the art duties on the Scud spin-off comic, La Cosa Nostroid.

Clayton's self created comic book Dr. Grave was published by California based publisher Slave Labor Graphics. Dr.Grave has been revived and is now published by the independent California based Antix Press.

Comics work includes:

• La Cosa Nostroid #2-9 (with writer Dan Harmon, Fireman Press, 1996—1998)
• Dr. Grave #1-6 (script and art, Slave Labor Graphics, 2000—2001)