Unlike the book, the movie doesn’t introduce Mattie as an old woman telling a story of her childhood, but instead begins and ends in late 1880, when Mattie is 14. In the book, Mattie remains the central character throughout; in the movie Rooster Cogburn gets an equal share of the limelight. The film also downplays the novel's biblical tone and adds a hint of romance between Mattie and La Boeuf. La Boeuf also does not die in the novel, but survives his head injury. Another significant difference from Portis' tale is that Mattie has her arm amputated as a result of the rattlesnake attack, in contrast to the final scene in the film where Kim Darby is seen with only a sling on her arm—indicating that she is recovering from the snake bites and intact physically. The novel's conclusion makes the reader aware that the story has been recounted by Mattie as an elderly, one-armed woman who never married.
In the book, Tom Chaney was a young man; Mattie guessed his age to be around 25. Jeff Corey, who played Chaney in the movie, was 55 at the time. In the movie, La Boeuf claims to have a girl in Texas who would "look with favor" on his capture of Tom Chaney. In the book, La Boeuf made no mention of a girlfriend; his motive for capturing Chaney was purely financial.
In the book, Rooster Cogburn had a mustache and did not wear an eye patch, though he had only one eye. In his fight with Ned Pepper, he wielded two Navy six-shooters. In the movie, Wayne carried a six-shooter in his left hand and his trademark large-loop rifle in the other. The character of Rooster was supposed to be around 40 in the novel; in the film, he was played by 61-year-old Wayne.
In the book, Mattie has her arm amputated due to the snakebite and break. Rooster pays her a visit while she is recovering from the procedure but is too sedated to remember. She tries to meet him 25 years later while he is traveling in a wild west show but he passes away a few days before they can meet. She has his remains exhumed and reinterred in her family plot.
Also, the film's Colorado location and mountain scenery are in sharp contrast to the script's references to place names in Arkansas and Oklahoma. Further, the film is set in autumn, while the book clearly sets the story in winter, with snow on the ground outside the dugout where Quincy and Moon awaited Pepper's gang. In the book, when Mattie falls into the snake pit she faces a ball of snakes and disturbs them in their winter quarters. In the film Mattie faces a single rattlesnake.