Blue had no theatrical experience when he came to the screen. His first movie was The Birth of a Nation (1915), in which he was a stuntman and an extra. Next, he played another small part in Intolerance (1916). He also was a stuntman or stand-in for Sir Herbert Beerbohm Tree during the making of Macbeth (1916). Gradually moving to supporting roles for both D. W. Griffith and Cecil B. DeMille, Blue earned his breakthrough role as Danton in Orphans of the Storm, starring sisters Lillian and Dorothy Gish. Then, he rose to stardom as a rugged romantic lead along with top leading actresses such as Clara Bow, Gloria Swanson, and Norma Shearer. He was most often partnered with Marie Prevost, with whom he made several films in the mid-1920s at Warner Bros. Blue's finest silent-screen performance was as the alcoholic Doctor who finds paradise in MGM's White Shadows in the South Seas (1928). Blue became one of the few silent stars to survive the talkie revolution; however, he lost his Investments in the stock market crash of 1929.

Blue divorced his first wife in 1923 and married Tova Jansen in 1924. He had two children, Barbara Ann and Richard Monte. During the later part of his life, Blue was an active Mason and the advance man for the Hamid-Morton Shrine Circus; while on Business in Milwaukee, Wisconsin, he had a heart attack because of complications from influenza and died at the age of 76. He is interred at Forest Lawn Memorial Park in Glendale, California alongside his mother-in-law, Actress, Bodil Rosing.

He rebuilt his career as a character actor, working until his retirement from films in 1954, though he continued playing character roles in various television series until 1960, mostly Westerns, such as Annie Oakley, starring Gail Davis and Brad Johnson.

For his contributions to the motion pictures industry, Monte Blue received a star on the Hollywood Walk of Fame at 6290 Hollywood Boulevard on February 8, 1960.