De Vol wrote the scores for many Hollywood movies, receiving Academy Award nominations for four of them: Pillow Talk (1959), Hush… Hush, Sweet Charlotte (1964), Cat Ballou (1965) and Guess Who's Coming to Dinner (1967).

Other familiar movies which featured work by De Vol include What Ever Happened to Baby Jane? (1962), Send Me No Flowers (1964), The Flight of the Phoenix (1965), The Dirty Dozen (1967), Krakatoa, East of Java (1969), Emperor of the North Pole (1973), Herbie Goes to Monte Carlo (1977), The Frisco Kid (1979) and Herbie Goes Bananas (1980).

De Vol also composed the jingle for the Screen Gems' Dancing Sticks on YouTube logo (1963–1965), which appeared on all television series produced by the television division of Columbia Pictures. Television work

De Vol was musical director (and occasionally seen) on Edgar Bergen's CBS Television prime-time game show Do You Trust Your Wife? (1956-1957). "Frank De Vol's orchestra" was featured on the NBC Television prime-time musical variety series The Lux Show Starring Rosemary Clooney (1957-1958). During this time, he appeared on The Betty White Show (1954) and Rod Cameron's syndicated State Trooper. His later appearances were on Fernwood 2 Night (1977) and America 2-Night (1978).

De Vol is best recognized for his television theme tunes, like Family Affair, Gidget, The Brady Bunch and My Three Sons. The My Three Sons theme was musically complex, with a piano playing a triplet obbligato over the melody in 4/4 time, and was a hit single in 1961. He composed scores for episodes of McCloud and The Love Boat, amongst other work for television.

Beginning in 1969, "The Fuzz" became the theme song of Brazilian television newscast Jornal Nacional. KOOL-TV (later KTSP, now KSAZ-TV) was the first television station to use the song. WKBW-TV also used the theme music for the first version of what would eventually become known as Eyewitness News. It would later be replaced by the Action News theme Move Closer to Your World.