Stanley Kubrick initially approached Arthur C. Clarke by saying that he wanted to make "the proverbial good science-fiction movie". Clarke suggested that his story "The Sentinel" (1948) about finding an alien artifact on the moon, would provide a suitable premise. Clarke had written it for a BBC competition, but it didn't even make the shortlist. The movie's opening scene has elements in common with Clarke's story "Encounter at Dawn," and the ending is arguably related to his beloved novel "Childhood's End." The screenplay was written primarily by Kubrick and the novel primarily by Clarke, each working simultaneously and also providing feedback to the other. As the story went through many revisions, changes in the novel were taken over into the screenplay and vice versa. The official records say that the screenplay was written in 58 days (13 October 1965-9 December 1965). Shooting began with the "Monolith on the Moon" scene on 29 December 1965. It was undecided whether film or novel would be released first; in the end it was the film. Kubrick was to have been credited as second author of the novel, but in the end was not. It is believed that Kubrick deliberately withheld his approval of the novel as to not hurt the release of the film.

In the premier screening of the film, 241 people walked out of the theater, including Rock Hudson who said "Will someone tell me what the hell this is about?" Arthur C. Clarke once said, "If you understand '2001' completely, we failed. We wanted to raise far more questions than we answered."

According to Katharina Kubrick, Stanley Kubrick provided the breathing heard in the spacesuits.

Stanley Kubrick had several tons of sand imported, washed, and painted for the moon surface scenes.

The carry-on bags belonging to Russian space scientists with whom Dr. Floyd shares a drink are marked Aeroflot (in Cyrillic), still today the Russian national airline.