Although the novel and film were developed simultaneously, the novel follows early drafts of the film, from which the final version of the film deviated. These changes were often for practical reasons relating to what could be filmed economically, and a few were due to differences of opinion between Kubrick and Clarke. The most notable differences are a change in the destination planet from Saturn to Jupiter, and the nature of the sequence of events leading to HAL's demise. Stylistic differences may be more important than content differences. Of lesser importance are the appearance of the monolith, the age of HAL, and the novel giving names to various spacecraft, prehistoric apes, and HAL's inventor.
Stylistically, the novel generally fleshes out and makes concrete many events left somewhat enigmatic in the film, as has been noted by many observers. Vincent LeBrutto has noted that the novel has "strong narrative structure" which fleshes out the story, while the film is a mainly visual experience where much remains "symbolic". Randy Rasmussen has noted that the personality of Heywood Floyd is different; in Clarke's novel, he finds space travel thrilling, acting almost as a "spokesman for Clarke", whereas in the film, he experiences space travel as "routine" and "tedious".
In the film, Discovery's mission is to Jupiter, not Saturn. Kubrick used Jupiter because he and special effects supervisor Douglas Trumbull could not decide on what they considered to be a convincing model of Saturn's rings for the film. Clarke went on to replace Saturn with Jupiter in the novel's sequel 2010: Odyssey Two. Trumbull later developed a more convincing image of Saturn for his own directorial debut Silent Running.
The general sequence of the showdown with HAL is different in the film from in the book. HAL's initial assertion that the AE-35 unit will fail comes in the film after an extended conversation with David Bowman about the odd and "melodramatic" "mysteries" and "secrecy" surrounding the mission, motivated officially because HAL is required to draw up and send to Earth a crew psychology report. In the novel it is during the birthday message to Frank Poole.
In the film, Bowman and Poole decide on their own to disconnect HAL in context of a plan to restore the allegedly failing antenna unit. If it does not fail, HAL will be shown to be malfunctioning. HAL discovers the plan by reading their lips through the EVA pod window. In Clarke's novel, ground control orders Bowman and Poole to disconnect HAL, should he prove to be malfunctioning a second time by predicting that the second unit is going to go bad.
However, in Clarke's novel, after Poole's death, Bowman tries waking up the other crew members, whereupon HAL opens both the internal and external airlock doors, suffocating these three and almost killing Bowman. The film has Bowman, after Poole's murder, go out to rescue him. HAL denies him reentry and kills the hibernating crew members by turning off their life-support. In the sequel 2010: Odyssey Two, however, the recounting of the Discovery One mission is changed to the film version.
The film is generally far more enigmatic about the reason for HAL's failure, while the novel spells out that HAL is caught up in an internal conflict because he is ordered to lie about the purpose of the mission.
Because of what photographed well, the appearance of the monolith that guided Moon-watcher and the other 'man-apes' at the beginning of the story was changed from novel to film. In the novel, this monolith is a transparent crystal; In the film, it is solid black. The TMA1 and TMA2 monoliths were unchanged.
While it is stated in the book that the ratio of the dimensions of the monolith are supposed to be 1:4:9, or the first 3 integral numbers squared, the shape of the actual monolith seen in the movie does not conform to this ratio. A ratio of 1:4:9 would produce an object that appears thick, wide, and squat. Kubrick wanted something taller and thinner, which he felt would be more imposing. Measurements taken from movie frames show that the movie monolith has dimensions approximately in the ratio 0.65:4:9 or 1:6:14.
In the book, HAL became operational on 12 January 1997, but in the movie the year is given as 1992. It has been thought that Kubrick wanted HAL to be the same age as a young bright child, nine years old.
The famous quote that opens the film sequel 2010: The Year We Make Contact—"My God—it's full of stars!"—is actually not in the 2001 film, although it is in the 2001 book.