We open in 1851. A wagon train is heading west, but Thomas Dunson (John Wayne) wants to head south with his cow and bull and start a ranch. He argues with the wagon train leader, and Dunson leaves with his friend Groot (Walter Brennan). Dunson's girl Fen (Colleen Gray) wants to go with him, but he insists it will be too hard, and he will send for her. He gives her his mother's bracelet off his own wrist as a token of his love.
Hours later, Dunson and Groot see a lot of smoke, and realize that the wagon train is being burned by Indians. They are too far to do anything to help, so they wait for the attack to reach them. In the night, the Indians attack, and Dunson and Groot fight them off. Dunson kills one Indian in hand-to-hand combat, and realizes afterwards that he is wearing the bracelet. Dunson knows his girl is dead.
The next morning, a dazed boy of about 14 wanders up to them, babbling about burning and killing. After a tense confrontation, they help him come to his senses, and he joins them. They cross the Red River and travel south through Texas, finally finding a spot Dunson feels is perfect. Dunson tells the boy (Matt Garth) and Groot that he will brand his cattle with the Red River D symbol. Matt wants an M added but Dunson says he'll have to earn it.
Shortly after they begin branding their cattle, two men working for Don Diego arrive, telling them that they are on Diego's land. Diego has, they say, 600 kilometers of land and lives south of the Rio Grande. Dunson tells them that from now on, he owns the portion north of the Rio Grande. When one of Diego's men draws, Dunson kills him and sends the message back to Diego with the surviving man.
Fourteen years pass, and Matt is now played by Montgomery Clift. The Civil War has impoverished the South, and although Dunson has the biggest cattle ranch in Texas, he's broke because no one in the South can buy beef. Dunson determines to start the biggest cattle drive in history, over 9,000 head north to Missouri, where people are buying beef. They going will be hard.
Groot will drive the chuckwagon and be cook for the journey. Joining the team is Cherry Valance (John Ireland). Both Cherry and Matt are famous sharpshooters, and they size each other up with interest. Also on the team is a gentle stutterer named Dan Latimer and a guy named Bunk who has a sweet tooth, and often sneaks up to the chuckwagon to steal sugar.
Dunson drives the men hard. There are stories of several ranchers who have attempted to get to Missouri and been ambushed and murdered. Cherry has heard that the railroad has reached Abilene, Kansas and the going is safer, but Dunson refuses to change his planned route because Cherry hasn't seen it with his own eyes.
About 160 miles out, it's a tense night and coyotes are making the cattle nervous. The men keep as quiet as they can to keep from spooking the cattle, but Bunk, stealing sugar again, knocks over a bunch of pots and pans. A stampede starts. Dan Latimer is killed, one of the grub wagons is destroyed, and about 400 head of cattle are lost. Furious, Dunson wants to whip Bunk, but Bunk refuses and draws. Dunson is about to kill him, but Matt is faster on the draw and shoots to wound. Bunk is sent back home.
The journey grows increasingly tense and sullen. At half-rations because of the loss of the grub wagon, the men are hungry and exhausted. Many want to leave but Dunson holds them to their contract. There's a gun battle. One of the men is killed and Dunson is wounded in the leg. That night, 3 men desert while Dunson is asleep. Dunson sends Cherry after them, and he drives the men as hard as he can, keeping them exhausted so they'll be too tired to sneak off in the night.
A man arrives, half dead with exhaustion and hunger, with a deep rope burn around his neck. He, too, had been part of a cattle drive to Missouri, and they were ambushed and murdered. He only survived because the rope around his neck frayed. He says he's met a scout who tells him the railroad is in Abilene, but again, Dunson asks if the scout saw the railroad himself, and when the man doesn't remember, Dunson says they're heading for Missouri.
After three days, Cherry comes back with two of the deserters; the third he's had to kill. Dunson says he intends to hang the men, but Matt stops him, and when he's about to draw on Matt, Cherry shoots him in the hand. He takes over the cattle drive, telling Dunson he's leaving him behind and that they will head to Abilene. Dunson tells Matt he will come after him and kill him.
From then on, the men are all nervous and jumpy, waiting for Dunson to approach them from behind.
They find a cow dead, with Apache arrows and Matt sends Cherry and Buster (Noah Beery) out ahead to scout.
Buster comes back full of excitement. About 12 miles ahead there's a wagon train with food and coffee and women. Now they take their cattle ahead eagerly, but they soon see the wagon train under Apache attack. They come to the rescue and Matt meets Tess (Joanne Dru). They fall in love as it begins to rain. Soon the rain becomes so hard and heavy that the river may flood and trap them. Matt takes the cattle on, leaving Tess behind.
Dunson meets Tess's wagon train and they talk. She is unable to stop Dunson from going after Matt, even offering her body as a bribe, and even ready to draw on him. At last she asks him to take her with him, explaining how it tore her apart when Matt left. Dunson realizes her words echo his dead love Fen's words, and he agrees.
Arriving in Abilene, Matt and his men discover that the Kansans are eager for beef and the price is high. They are greeted like heroes and Matt pays all his men in cash, taking the rest of the payment in a check made out to Dunson. When Matt goes to his hotel room he finds Tess waiting for him. Dunson is outside town and will come in the morning she says, and they spend the night together.
When Dunson arrives Cherry tries to stop him, and they shoot each other. Cherry falls, and Dunson keeps walking. Matt faces him down and refuses to draw, even when Dunson shoots several shots, closer and closer, including his hat, and finally grazing his cheek. Matt lets Dunson punch him twice, then fights back, and the two tussle until Tess draws her gun and stops them.
Dunson tells Matt he will add an M to the brand when they get home.