Duff worked locally in Seattle-area theater until entering the United States Army Air Corps during World War II.

[3][4] Duff was signed to a long-term contract with Universal, and made his film debut alongside Burt Lancaster as an inmate in 1947's Brute Force.

The movie was produced by Mark Hellinger and directed by Jules Dassin, who gave Duff a bigger role in their next film, The Naked City (1948).

More substantial roles soon followed, with Duff taking the lead in numerous Westerns and films noir including Illegal Entry, Red Canyon, Johnny Stool Pigeon, Calamity Jane and Sam Bass (all 1949);[6]Spy Hunt, Shakedown and Woman in Hiding (all 1950).

[8] Duff appeared in the 1952 film That Kind of Girl (aka Models Inc),[9] and also featured in Spaceways, and Roar of the Crowd (both 1953), the latter for Monogram Pictures, which ultimately made Jennifer (also 1953), the second movie in which he starred alongside his wife.

His other film appearances beside his wife; Don Siegel's Private Hell 36 (1954); Lewis Seiler's Women's Prison (1955), and Fritz Lang's While the City Sleeps (1956) continued Duff's successful run of movies during the 1950s.

[10] Other TV roles included an appearance in NBC's Western series Bonanza, playing a young Samuel Langhorne Clemens in his early life in the West as a satirical and crusading journalist, in the first-season episode "Enter Mark Twain".

"[11]: 428 Duff had the lead role in the short-lived TV series Dante (which ran for only one season; 1960–61),[10] but found greater success as Detective Sergeant Sam Stone in the ABC police drama Felony Squad (1966–69).

In 1971 Duff appeared as Stuart Masters in The Men from Shiloh (the retitled final season of the TV Western The Virginian) in the episode titled "The Town Killer".

In 1990, shortly before his death, Duff made his final acting appearances in the TV series Midnight Caller and The Golden Girls, and the film Too Much Sun.