While in Austria filming Where Eagles Dare (1968), Clint Eastwood was approached with the script by Elizabeth Taylor, Richard Burton's wife at the time, with the notion of starring together in the film. However, Universal Pictures was unwilling to pay Taylor's high salary.
The film's title is actually a pun, of sorts. Though Sara's initial transportation is a mule, she soon trades the now-lame mule for a burro. The second "mule" of the title is actually Eastwood's character, Hogan, whom Sara complains is stubborn and even refers to him as "Mr. Mule" in one scene.
The Finnish title of the film is "Kourallinen dynamiittia", which translates into English as "Fistful of Dynamite". This is actually the alternative English title of dollar-trilogy director Sergio Leone's film Duck, You Sucker (1971).
The trivia item below may give away important plot points.
Shirley MacLaine wrote that since this was filmed in Mexico, it took substantial time to send the film to California for processing and return it for dailies. When MacLaine finally saw the dailies, she was appalled at how overstated her false eyelashes looked, as she was playing a hooker posing as a nun. She regretted that she could not remove them for the rest of the filming because the footage would not match.