DeLuise made his film debut in 1979 opposite his father in the 1979 comedy Hot Stuff. In 1990 he landed his first major role with the Fox hit series 21 Jump Street. He played Officer Joey Penhall, the younger brother of Peter DeLuise's Officer Doug Penhall. He also starred with his brother Peter on SeaQuest DSV where he played Tony Piccolo from 1994 to 1996.
