Henry Fonda originated the Broadway title role and performed it over 1,000 times. He even won a Tony award for it! However, thinking Fonda might be too old for the part, the film’s producers considered Montgomery Clift, William Holden, and Marlon Brando. Brando accepted the role, but dropped out. Thankfully, director John Ford refused to do the film unless Fonda reprised the part. Ford said, "[Fonda had] a fine war record. He never advertised the fact... I'm very proud of him. He was in the Navy."

John Ford had to undergo surgery during production and Mervyn LeRoy and Josh Logan stepped in to help finish the film. Despite having to leave, Ford was a major help to the film. Originally, the US Navy disliked James Cagney’s character, but Ford, who was a WWII veteran, convinced them to approve the script. As a result, they were able to use Navy resources. "He's a great man's director," Fonda said of Ford.

Ford personally offered James Cagney the role. They had previously worked together on What Price Glory. Cagney said, "I did it for a lark, and it was one of the easiest pictures I ever made. Everyone else had to jump and holler all the time. I just pulled my cap over my eyes, walked on deck, barked a command or two, and then went home." Cagney liked to play his guitar on the set in Hawaii.

Mister Roberts was nominated for three Oscars including Best Picture, Best Sound, and Best Supporting Actor. Jack Lemmon took home his first Academy Award for the film. In his speech, Lemmon said, "Since I have been in this end of entertainment industry, I have been very fortunate in working with only the highest of professionals. I would like to thank them for the help and the opportunities they gave me.” Interestingly, Frank Sinatra was actually considered for Lemmon’s role, but producers nixed the idea because they wanted a younger actor.