While playing high school football, a stage manager from a touring theatrical stock company noticed the tall, handsome youth and hired him as a bit player.

Another source states "Grace George hired his entire high school football team as supers for a Shakespearean play.

[citation needed] Calhern began working in silent films for director Lois Weber in the early 1920s, the most notable being The Blot (1921).

He returned to films early in the sound era where he was primarily cast as a character actor, while he continued to play leading roles on the stage.

Among Calhern's notable screen portrayals were as the partner in crime to Spencer Tracy and Bette Davis in 20,000 Years in Sing Sing (1932), as Ambassador Trentino in the classic Marx Brothers comedy Duck Soup (1933), as Major Dort in The Life of Emile Zola (1937), and as the spy boss of Cary Grant in Alfred Hitchcock's Notorious (1946).

He was subsequently cast in the title role of Joseph L. Mankiewicz’s 1953 all-star film version of Shakespeare’s Julius Caesar, earning more praise.

His performance as cheerfully lecherous Uncle Willie in High Society (1956), a musical remake of The Philadelphia Story, was his final film appearance.