The son of Italian immigrants, Manhattan-born Joe DeSantis started out in 1931 as an actor and announcer for Italian-language radio programs; that same year, he made his first Broadway appearance in Sierna, likewise performed in Italian. DeSantis did not act in English until he was hired for the Walter Hampden troupe in 1932. Throughout the late 1930s and 1940s, DeSantis was active in network radio (where he specialized in dialect parts), regional theatre, and government-funded acting projects. After his inaugural film appearance in 1949's Slattery's Hurricane, DeSantis remained on call for roles requiring muscle and menace. His film credits include I Want to Live (1958), Al Capone (1959) (as Big Jim Colosimo), The George Raft Story (1960), Beau Geste (1966), The Professionals (1966) and Little Cigars (1973). Joe DeSantis was a regular on the pioneering 1949 television series Photocrime (1949), and was narrator of the 1950 melodramatic TV anthology The Trap.