His first non-Our Gang role was in 1931, when his uncle Norman Taurog hired him to star in Skippy, for which he was nominated for the Academy Award for Best Actor (the youngest actor ever, 10, to receive the nomination).

The movie catapulted young Jackie into super-stardom. Our Gang producer Hal Roach sold Jackie's contract to Metro-Goldwyn-Mayer in mid-1931, as he felt the youngster would have a better future in features. He began a long on-screen relationship with actor Wallace Beery in such films as The Champ (1931), The Bowery (1933), Treasure Island (1934), and O'Shaughnessy's Boy (1935). A legion of film critics and fans have lauded the relationship between the two as an example of classical movie magic. However, Cooper later gave the real story. He said Beery was a violent, foul-mouthed drunkard who was disliked by those he worked with. Cooper even said Beery had been abusive towards him and he could not stand working with him. He said Beery was one of the cruelest most sadistic people he had ever known.

Cooper had problems finding roles as he became an adolescent, and he served in World War II, so his career was at a nadir when he starred in two popular television series, The People's Choice and Hennesey. It was his television acting that convinced him that he could become a director, and he successfully moved behind the camera, to become one of the busier television directors, for which he won Emmy Awards.

Later in the 1970s, he found renewed fame as Clark Kent's editor, Perry White, in the Superman feature film series starring Christopher Reeve.

His autobiography, Please Don't Shoot My Dog, was published in 1981. The title comes from Norman Taurog's threat to shoot young Jackie's dog if he couldn't cry in Skippy.

Cooper has a star on the Hollywood Walk of Fame at 1501 Vine Street.