Orson Welles made this film during one of the several breaks in the filming of his own Othello (1951) (which he began in 1949 and which was not finished until 1951). Everett Sloane, whom he had cast as Iago in his own film, came with him into this one, with his role built up by extensive script rewrites by the uncredited Welles. This may have been partly an attempt by Welles to ensure that Sloane remained with him to complete "Othello" --- but, in fact, Sloane walked off the film, creating an extra difficulty for Welles, who never forgave him.
The expense of making a film in Italy, using an international cast and many authentic locations was daunting to Darryl F. Zanuck, who, after some soul-searching, decided, as an economic measure that the film should be made in black-and-white, not color. He later expressed regret about this decision.
The motto "The die is cast" on Cesare Borgia's palace was famous for having been spoken more than 1500 years earlier by Julius Caesar (Gaio Giulio Cesare) when he crossed the Rubicon to make war on Rome.
Reportedly Tyrone Power heavily canvassed 20th Century Fox to cast his wife-to-be Linda Christian as the film's female lead. Married from 1949 to 1956, Power and Christian would never be cinematic cast-mates: Christian did audition to be Power's leading lady in The Mississippi Gambler (1953) --- which Power made on loan-out to Universal Pictures --- but Universal gave the film's female lead role to its own contract player Piper Laurie.
Female lead Wanda Hendrix was loaned to 20th Century Fox by Paramount Pictures in return for Fox loaning Victor Mature to Paramount to headline Samson and Delilah (1949).