Todd Haynes needed to get approval from Bob Dylan to use his music, since (unlike in his Velvet Goldmine (1998) where David Bowie did not give his permission for his music) he felt the film would not work without it. At the encouragement of Dylan's manager, Haynes wrote a one-page summary of his concept and the characters, which Dylan approved. It took another 6 years to get the film made due to funding difficulties.
Different sections of the film were inspired by different cinematic sources. The "Jude" section was inspired by 8½ (1963), the "Billy" section was inspired by the so-called "hippie westerns" of the late 60s and early 70s (such as Sam Peckinpah's films) and the "Robbie" section was inspired by the films of Jean-Luc Godard, especially Masculine Feminine (1966).
Colin Farrell was originally cast as Robbie Clark. He dropped out of the film to admit himself into rehab for a dependency on back pain medication. Heath Ledger replaced him. Farrell would later take over for Ledger in The Imaginarium of Doctor Parnassus (2009) after Ledger's death.
Cate Blanchett wore a sock down her trousers to play Bob Dylan. The actress said it "helped me walk like a man."
Kris Kristofferson, who narrates the film, is a friend of Bob Dylan. They were both in Pat Garrett & Billy the Kid (1973).