Stanley Kramer originally had Sidney Poitier and Marlon Brando in mind for the two protagonists. Both were interested but only Poitier was available. Brando was caught up in filming Mutiny on the Bounty, a film with a highly troubled and seemingly endless shoot. As the start date for The Defiant Ones loomed, Kramer had no option but to start looking at other actors.

Robert Mitchum turned down the Tony Curtis' role. Mitchum, a real-life veteran of a Southern chain gang, said that he didn't believe the premise that a black and white man would be chained together, as such a thing would never happen in the very strictly segregated South. Over the years, this reason was corrupted to the point where many people now believe Mitchum turned down the role because he didn't want to be chained to a black man, an absolute falsehood. Curtis repeated the inaccurate story in his autobiography, but since has recanted after it was explained to him.

Elvis Presley wanted the role of Joker Jackson, hoping to co-star with Sammy Davis Jr. (who had been first choice for the role of Noah Cullen) but was persuaded by his manager not to do the film.

Tony Curtis insisted that Sidney Poitier received top billing.

Tony Curtis was very keen to make the film as he saw it as an opportunity to break out of the mindless, pretty boy roles he was usually assigned. Director Stanley Kramer initially had some misgivings but ultimately relented.

A technical advisor on board during filming had to go uncredited, because he was a real-life chain gang escapee who was still a wanted man.

Charlie Potatoes is an old slang term (more common in the USA than the UK) for someone who is on top of the world, usually in terms of money or popularity.

Other than Sidney Poitier's singing, all of the music in the film comes from radios.

The film's co-writers, Nedrick Young and Harold Jacob Smith, were cast as the prison truck drivers, with the writing credits below their faces, because Young was blacklisted and writing under a pseudonym at the time and producer Stanley Kramer wanted to identify them truthfully.

The young man with the transistor radio is played by Our Gang graduate Carl 'Alfalfa' Switzer; this was Switzer's final screen appearance before his untimely death in a shooting incident.