Calhern was married four times, to Ilka Chase (1900–1978) from 1926 to 1927, Julia Hoyt (1897–1955) from 1927 to 1932, Natalie Schafer (1900–1991) from 1933 to 1942, and Marianne Stewart (1922–1992) from 1946 to 1955. All four marriages ended in divorce.
Calhern began working in silent films for Director Lois Weber in the early 1920s; the most notable being The Blot in 1921. A 1921 newspaper article commented, "The new arrival in stardom is Louis Calhern, who, until Miss Weber engaged him to enact the leading male role in What's Worth While?, had been playing leads in the Morosco Stock company of Los Angeles."
In 1923 Calhern left the movies, but would return to the screen eight years later after the advent of sound pictures. He was primarily cast as a character actor in films while he continued to play leading roles on the stage. He reached his peak in the 1950s as a Metro-Goldwyn-Mayer contract player. Among his most memorable screen roles were Ambassador Trentino in the Marx Brothers classic Duck Soup (1933) and three that he appeared in at MGM in 1950: a singing role as Buffalo Bill in the film version of the musical Annie Get Your Gun, the double-crossing Lawyer and sugar-daddy to Marilyn Monroe in John Huston's film noir The Asphalt Jungle, and his Oscar-nominated performance as Oliver Wendell Holmes in The Magnificent Yankee (re-creating his role from the Broadway stage). He was also praised for his portrayal of the title role in the John Houseman production of Julius Caesar (adapted from the Shakespeare play) in 1953, directed by Joseph L. Mankiewicz. Calhern also played the role of the devious George Caswell, the manipulative board member of Tredway Corporation in the 1954 production of Executive Suite.
Calhern's other film roles included the grandfather in The Red Pony (1949), adapted from the novel by John Steinbeck and starring Robert Mitchum, and the spy boss of Cary Grant in the Alfred Hitchcock suspense classic Notorious (1946). A performance as Uncle Willie in High Society (1956), a musical remake of The Philadelphia Story, turned out to be his final film.
Calhern's burgeoning career was interrupted by the war, and he served overseas in the 143rd Field Artillery of the United States Army during World War I.
