A scene when Prudence locks herself in the closet and has to be serenaded out by the other cast members - is a reference to a real occurrence in 1968 at the ashram of Maharishi Mahesh Yogi in India where The Beatles, Mia Farrow, Donovan, and others were studying. Mia Farrow's sister, Prudence, was reclusive and did not leave her living quarters to join the other students, inspiring John Lennon to write the song "Dear Prudence." The film also uses the song as a subtle reference to the fictional Prudence character's reluctance to 'come out of the closet' in relation to her sexual orientation.

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In an interview, Evan Rachel Wood and Jim Sturgess said that they were at dinner one day and heard that Ringo Starr would be attending a screening in town. They promptly booked it to the theater and watched their movie with one of the original Beatles. Sturgess then asked Starr what he thought of it. He said he enjoyed it very much.

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Sadie, with her fiery red hair and passionate temper, is a reference to Janis Joplin. Sadie is even seen drinking directly from a Jack Daniels bottle during her downward spiral, an action that Janis did regularly with Southern Comfort. Even Janis' throaty singing voice is used by Sadie in the movie.

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Jude's life progression is similar to John Lennon's. As John Lennon did, Jude first lived in Liverpool then soon after that moved to New York City to work as an artist like Lennon. Jude then encounters trouble with the law and is deported (Lennon was arrested as well, but an attempt to deport him failed).

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Bono wears a hat with the word YES written across it in reference to John Lennon and Yoko Ono's first meeting in her art studio, where he found a ladder propped against a white wall. After climbing the ladder at the top he found the word "yes". When he asked Yoko why she smiled and said "would you rather it tell you no?"

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The non-existent joint in the "With a Little Help From My Friends" sequence is non-existent to ensure that the movie is not R-rated.