After appearing on the Broadway stage and live television, Middleton began appearing in films in 1954, and in film opposite Humphrey Bogart in The Desperate Hours (1955), Danny Kaye in The Court Jester (1955), Gary Cooper in Friendly Persuasion (1956), Richard Egan and Elvis Presley in Love Me Tender (1956), Dorothy Malone and Robert Stack in The Tarnished Angels (1958), Robert Taylor and Richard Widmark in The Law and Jake Wade (1958), and Dean Martin in Career (1959).

He played a dishonest candidate for the United States House of Representatives in an episode of ABC's The Real McCoys, starring Walter Brennan and Richard Crenna.

In 1956, he guest starred on James Arness’s TV Western series Gunsmoke, playing the title character in the episode “Dutch George” (S1E32), a flamboyant career horse thief who was friends with Matt Dillon in their wilder younger days (this episode unveiled some of Dillon’s shadier past, once being a young man who also might have stolen, who at a yet to be revealed crossroad in life, opted to be a lawman).

[citation needed] Middleton was cast in ten episodes of the ABC family Western drama, The Monroes, with costars Michael Anderson, Jr., and Barbara Hershey.

That same year, he portrayed the highly sympathetic but fiercely dedicated state executioner in an episode of Thriller (U.S. TV series) entitled "Guillotine".

[10] Other significant film roles included The Court Jester (1955) as a grim and determined knight who jousts with Danny Kaye in the famous "pellet with the poison" sequence, and as Edwin M. Stanton in The Lincoln Conspiracy (1977).

Middleton guest-starred on Get Smart as the KAOS villain "The Whip", intent on hypnotizing Agent 86 in the 1970 series finale "I Am Curiously Yellow".