Born Emanuel Goldenberg to a Yiddish-speaking Jewish family in Bucharest, he emigrated with his family to New York in 1903. He attended Townsend Harris High School and then City College of New York, but an interest in acting led to him winning an American Academy of Dramatic Arts scholarship, where he changed his name to Edward G. Robinson (the G. signifying his original last name). He began his acting career in 1913 and made his Broadway debut in 1915. He made his film debut in a very minor and uncredited role in 1916; in 1923 he made his named debut as E. G. Robinson in The Bright Shawl. One of many actors who saw his career flourish in the new sound film era rather than falter, he made only three films prior to 1930 but left his stage career that year and made fourteen films in 1930-32. He married the actress Gladys Lloyd in 1927.

A sensational performance as the gangster Rico Bandello in Little Caesar (1931) led to him being typecast as a 'tough' for much of his early career in works such as Five Star Final (1931), Smart Money (1931; his only movie with James Cagney), Tiger Shark (1932), Kid Galahad (1937), and A Slight Case of Murder (1938). In the 1940s, after a good performance in Dr. Ehrlich's Magic Bullet (1940), he expanded into edgy psychological dramas including Double Indemnity (1944), The Woman in the Window (1945) and Scarlet Street (1945); but he continued to accept gangster roles such as that of Johnny Rocco in John Huston's classic Key Largo (1948), the last of five films he made with Humphrey Bogart, and the only one in which he took second billing to Bogart (although his name was listed to the right of Bogart's but a little higher in both the posters and the film itself, to equalize the billing a bit).

In the 1950s he was called to testify in front of the House Un-American Activities Committee and wound up blacklisted, even though he reluctantly named names, until Cecil B. DeMille finally cast him in The Ten Commandments (1956).

Robinson built up a very significant art collection that in 1956 he sold to Greek shipping tycoon, Stavros Niarchos in order to raise cash needed for his divorce settlement with Gladys Lloyd, which occurred at the end of his blacklist, when he was cash-strapped. That same year he returned to Broadway in Middle of the Night.

After DeMille brought Robinson back into movies, his most notable roles occurred in A Hole in the Head (1959) opposite Frank Sinatra and The Cincinnati Kid (1965), a superb Robinson showcase with Steve McQueen, a sort of poker-playing version of The Hustler, an earlier pool-shooting movie with Paul Newman in the McQueen part and Jackie Gleason as the older champion, similar to the one portrayed by Robinson in The Cincinnati Kid. Director Peter Bogdanovich was offered The Godfather in 1972 but turned it down, later remarking that he would've cast Robinson in the role later played by Marlon Brando. Robinson indeed tried to talk his way into the part (which was how he'd gotten to play Little Caesar forty years before), but Francis Coppola decided on Brando instead, over the initial objections of the studio.

Robinson was a hugely popular box-office draw in the 1930s and '40s and was able to avoid many flops over a career of over 90 films spanning 50 years. His last scene was a suicide sequence in the science fiction cult classic Soylent Green (1973) in which he dies in a euthanasia clinic while watching nature films on a wall-sized screen.

Never nominated for an Academy Award, in 1973 he was awarded an honorary Oscar in recognition that he had "achieved greatness as a player, a patron of the arts, and a dedicated citizen ... in sum, a Renaissance man"; sadly, he died from cancer at the age of 79 two months prior to the award ceremony.

He is interred at Beth El Cemetery in Queens, New York.