Starting work in radio in the late 1930s in California, Conrad went on to serve as a fighter pilot in World War II. He returned to the airwaves after the war, going on to accumulate over 7,000 roles in radio by his own estimate.

Conrad's deep, resonant voice led to a number of noteworthy roles in radio drama, most prominently his originating the role of Marshal Matt Dillon on the Western program Gunsmoke from 1952-61. He was considered for the role when the series was brought to television in 1955, but his increasing obesity led to the casting of James Arness. Other series to which Conrad contributed his talents included Escape, Suspense and The Damon Runyon Theater.

Among his various film roles, where he was usually cast as threatening figures, perhaps his most notable role was his first credited one, as one of the gunmen sent to eliminate Burt Lancaster in the 1946 film The Killers. He also appeared in Body and Soul (1947), Sorry, Wrong Number, Joan of Arc (both 1948), and The Naked Jungle (1954).

Moving to television in the 1960s, his first decade in the medium was largely marked by a return to voice work (most notably as narrator of The Fugitive from 1963-67) and the direction of Brainstorm in 1965; he narrated the Bullwinkle cartoons from 1959-64 (as "Bill Conrad"), and later performed the role of Denethor in the 1980 animated TV version of J. R. R. Tolkien's The Return of the King. But the 1970s saw him starring in the first of three detective series which would bring him an added measure of renown, Cannon, which ran from 1971-76. He later starred in both Nero Wolfe (1981) and Jake and the Fatman (1987-92).

Conrad died at age 73 in Los Angeles, California and is interred at Forest Lawn, Hollywood Hills Cemetery. He was elected to the Radio Hall of Fame in 1997.