The film's supporting cast features Walter Brennan, Joanne Dru, Coleen Gray, Harry Carey, John Ireland, Hank Worden, Noah Beery, Jr., Harry Carey, Jr. and Paul Fix. Borden Chase and Charles Schnee wrote the screenplay, based on Chase's original story (which was first serialized in The Saturday Evening Post in 1946 as "Blazing Guns on the Chisholm Trail").
Thomas Dunson (John Wayne) is a stubborn man who wants nothing more than to start up a successful cattle ranch in Texas. Shortly after he begins his journey to Texas with his trail hand Nadine Groot (Walter Brennan), Dunson learns that his love interest (Coleen Gray), whom he had told to stay behind with the California-bound wagon train with the understanding that he would send for her later, was killed in an Indian attack.
Despite this tragedy, Dunson and Groot press on. That night, Dunson and Groot, keeping watch, hear a group of Indians planning to attack them. They kill the Indians, and on the wrist of one, Dunson finds a bracelet he had been left by his late mother. One day before, he had presented it to his young love as he left the wagon train. The bracelet reappears significantly later in the film.
The next day, an orphaned boy named Matthew Garth (played as a boy by Mickey Kuhn and as an adult by Montgomery Clift) wanders into Dunson and Groot's camp, traumatized and babbling incoherently. He had been part of the wagon train Dunson had left, and had come back from finding a strayed cow to see the ruins of the train. He is the sole survivor of the wagon train. Dunson adopts him and ties the boy's cow to his wagon, alongside a bull Dunson already owned.
With only the bull and the cow, Dunson, Groot and the boy enter Texas by crossing the Red River. In search for land they travel through Texas, finally settling in deep South Texas near the Rio Grande. Upon arrival, Dunson proudly proclaims all the land about them as his own.
Two Mexican men appear on horseback and inform Dunson that the land already belongs to their boss, a Spanish grandee whose family held the land by patent from the King of Spain. Dunson dismisses this inconvenient fact and, thanks to a quicker draw in a showdown, kills one of the men and tells the other man to inform the Spanish don that Dunson now owns the land. Dunson names his new spread the Red River D, after his chosen cattle brand for his herd. Fatefully, he promises to add M (for Matt) to the brand, once Matt has earned it.
Fourteen years pass and Dunson now has a fully operational cattle ranch. With the help of Matt and Groot, his herd now numbers over ten thousand cattle, but he is also broke as a result of widespread poverty in the southern United States. Due to its loss of the American Civil War, the South cannot afford Dunson's beef. Dunson decides to drive his massive herd hundreds of miles north to the railhead at Sedalia, Missouri, where he believes they will fetch a good price.
After Dunson hires some extra men to help out with the drive, including professional gunman Cherry Valance (John Ireland), the perilous northward drive starts. Along the way, they encounter many troubles including a stampede sparked by one of the men, Bunk Kenneally (Ivan Parry), making a clatter while trying to steal sugar from the chuck wagon. This leads to the death of Dan Latimer (Harry Carey Jr). Despite Bunk knowing what he did caused all these problems, Dunson wants to make an example of him by whipping him; but when Bunk draws his gun in self-defense as Dunson is about to whip him, Matt shoots Bunk in the arm, knowing that Dunson would have shot to kill. The wounded Bunk is sent to make his way home on his own.
Continuing with the drive, Valance relates around the campfire one evening that the railroad has reached Abilene, Kansas, which is much closer than Sedalia. When Dunson confirms that Valance had not actually seen the railroad, he ignores what he regards as a rumor in favor of continuing on to Missouri.
Deeper problems arise when Dunson's tyrannical leadership style begins to affect the men. One of the two chuck wagons was destroyed in the stampede, causing morale to drop as the men live on nothing but beef and roasted grain "coffee". Dunson tells the men he is broke and cannot buy more supplies, even if they turned back to get them. When he announces he intends to lynch two men who had deserted the drive and taken a sack of flour and 100 rounds of ammunition with them and been recaptured by Cherry Valance, Matt rebels.
With the help of Valance and the other men, Matt takes control of the herd in order to drive it along the Chisholm Trail to the hoped-for railhead in Abilene, Kansas. Valance and Buster (Noah Berry Jr.) become his right hand men. Face to face, Dunson curses him and promises to kill him when next they meet. The drive turns toward Abilene, leaving the lightly injured Dunson behind with his horse and a few supplies. Matt and his men are well aware that Dunson will try to recruit a posse to pursue and attack them.
On the way to Abilene, Matt and his men repel an Indian attack on a wagon train made up of gamblers and dance hall girls. One of the people they save is Tess Millay (Joanne Dru), who falls in love with Matt. They spend a night together and he gives her Dunson's mother's bracelet, evidently given to Matt by Dunson in earlier years. Eager to beat Dunson to Abilene, he leaves early in the morning — the same way Dunson had left his lady love with the wagon train 14 years before.
Later Tess encounters Dunson, who has followed Matt's trail to the gamblers' wagon train. He sees her wearing his mother's bracelet. Weary and emotional, he tells Tess what he wants most of all is a son. She offers to bear him one if he will abandon his pursuit of Matthew Garth. Dunson sees in her the same anguish that his beloved had expressed when he left her. Despite that, he resumes the hunt. Tess Millay in her wagon accompanies him.
When Matt reaches Abilene, he finds the town has been eagerly awaiting the arrival of such a herd to buy and ship it east by rail. Unknowingly, he has completed the first cattle drive along what would become famous as the Chisholm Trail. He accepts an excellent offer for the cattle. He also meets Tess again, who has preceded Dunson into town.
Shortly thereafter, Dunson arrives in Abilene with his posse, to fulfill his vow to kill Matt. Cherry Valance tries to keep the two apart, but Dunson beats him to the draw, badly wounding him while Valance inflicts a flesh wound on Dunson. Dunson and Matt begin a furious fistfight, which Tess interrupts by drawing a gun on both men, shooting wildly and demanding that they realize the love that they share. Dunson and Matt see the error of their ways and make peace. The film ends with Dunson advising Matt to marry Tess, and telling Matt that he will incorporate an M into the Red River D brand as he had promised 14 years before, because he had earned it.
Red River was filmed in 1946, copyrighted in 1947, but not released until September 30, 1948. Footage from Red River was later incorporated into the opening montage of Wayne's last film, The Shootist, to illustrate the backstory of Wayne's character. The film was nominated for Academy Awards for Best Film Editing (Christian Nyby) and Best Writing, Motion Picture Story (Borden Chase). John Ford—who worked with Wayne on many films (such as Stagecoach, The Searchers and The Man Who Shot Liberty Valance)—was so impressed with Wayne's performance that he is reported to have said, "I didn’t know the big son of a bitch could act!" In June 2008, AFI listed Red River as the fifth-best film in the western genre.
Second unit director Arthur Rosson was given credit in the opening title crawl as co-director. He shot parts of the cattle drive and some action sequences.
The film's ending differed from that of the original story. In Chase's original Saturday Evening Post story, Valance shoots Dunson dead in Abilene and Matt takes his body back to Texas to be buried on the ranch.
During the production and while the film was still being shot, Howard Hawks was not satisfied with the editing and asked Christian Nyby to take over cutting duties. Nyby worked about 1 year on the project. After production, the pre-release version was 133 minutes and included book-style transitions. Howard Hawks felt this version was too long, and that the inserts in the book were both difficult to read and awkward, slowing down the pace of the film. He had a narration written and called Walter Brennan in to record it. They removed the book-style transitions and, together with Brennan's narration, tightened the running time and added a beneficial character intimacy to the film. This version was briefly available for television in the 1970s, but is believed to be lost.
Before this version could be released, Howard Hughes sued Howard Hawks, claiming that the climactic scene between Dunson and Matt was taken from the film The Outlaw (1943), which Hawks had worked on with Hughes. To resolve the issue, editor Nyby and Hughes went back and forth trimming, re-cutting, and re-inserting until a compromise was reached. This final product was the original theatrical version which was released at 127 minutes. For unknown reasons, the 127-minute theatrical version, which was preferred by Howard Hawks, was lost, and it was the 133-minute pre-release version which was seen on television broadcasts and home video releases for decades. The original theatrical cut was reassembled by Janus Films (in co-operation with UA parent company MGM) for their Criterion Collection Blu-ray/DVD release on May 27, 2014.
The song "Settle Down", by Dimitri Tiomkin (music) and Frederick Herbert (lyric), heard over the credits and at various places throughout the film score, was later adapted by Tiomkin, with a new lyric by Paul Francis Webster, as "My Rifle, My Pony, and Me" for the 1959 film Rio Bravo.
According to Variety the film earned $4,150,000 in rentals in North America in 1948.
Roger Ebert considered it one of the greatest Western films of all time.