With the advent of television, Joe became known as a skilled character actor who could play convincing dialect characters, mugs, suave heavies and emotional leads. He was active in such early television series as Playhouse 90, Studio One, Sheriff of Cochise, and he appeared regularly on the programs of Red Buttons, Martha Raye and Sid Caesar shows. In addition to many single performances on other series like Voyage to the Bottom of the Sea, Joe had a recurring presence in such shows as The Untouchables, 77 Sunset Strip, Perry Mason, Mission: Impossible, and in the westerns such as Sugarfoot, Daniel Boone, Gunsmoke, Sara, and Bonanza. De Santis made three guest appearances on Perry Mason; in two of the episodes he played the murder victim: George Castle in the 1958 episode, "The Case of the Long-Legged Models", and Melvin Slater in the 1959 episode, "The Case of the Borrowed Brunette". He was also cast as Louie Parker in the 1965 episode, "The Case of the Deadly Debt".