Based on a true story, John Colter becomes a legend during the early days of the American frontier due to his adventures in the Yellowstone region and encounters with dangers that lead to an arduous eleven-day, two-hundred mile flight across the wilderness in which he has only his wits to survive.
Three years earlier, Colter is a member of the Lewis and Clark Expedition that is trying to chart a northwest passage to the Pacific Ocean. Among the team is SERGEANT ORDWAY, who does not like Colter for mysterious reasons; JOHN POTTS, an affable drinker; GEORGE DROUILLARD, a French-Canadian who is Colter's closest friend; and the volatile TOUSSAINT CHARBONNEAU and his young wife SACAGAWEA, a member of the Shoshone tribe. As they head down the river, Colter tells Drouillard how he was disowned by his father GEORGE COLTER after he announced he didn't want to be a farmer. Colter seeks freedom on his own terms but his father warned him that he would fail. Colter has been determined ever since to prove his father wrong and volunteered for the expedition for the money and adventure.
Later, Colter reveals that he went to stay with his cousins after leaving his family, during which time he met SALLIE LOUCY, a vivacious young woman with him he fell in love. He is now uncertain if she is waiting for him back home. The men continue their arduous trek and have several adventures, including one on the river where Charbonneau nearly causes the boat to capsize. Colter has to intervene and threatens Charbonneau in the process, turning the man into an enemy. Later, while moving through a gully during a storm, Potts and Drouillard save Colter.
The expedition continues its journey and tensions continue to rise between Charbonneau and the others. Drouillard reveals that Charbonneau bought Sacagawea when she was thirteen and the men witness Charbonneau striking her. The group visits a Shoshone village where Sacagawea is ignored by the Chief even though he is her brother and, after a celebration, the men are lashed by Ordway for drunkenness. Later, the group reaches the mountains and the members realize there is no northwest passage. Nonetheless, they continue by foot hoping to reach the west coast.
Eventually, after more hardships, the group reaches the coastline of what will one day be Washington state. As it's nearing winter, they realize they must make camp and head back in the spring. During this time, Colter is nearly killed by Charbonneau while hunting but he stands up to the man and reveals him to be the coward that he is.
In the spring, the expedition start the trek home. They encounter the Blackfeet and the encounter soon turns violent. The men escape but know they have made enemies. Shortly after, Colter asks for permission to leave the expedition so he can work as a trapper for two locals he met in a village. Lewis grants the permission and Colter bids a fond farewell to his friends before heading into the wilderness.
Colter soon realizes he doesn't get along with the men who hired him and he takes his leave of them. He next helps settlers build Fort Raymond for the Missouri Fur Trading Company, where he impresses the owner, MANUEL LISA. Manuel asks him to head up trade negotiations with the Crow nation. Over the next several months, Colter builds a relationship with the Crow and explores the area that will one day be Yellowstone. He gains fame for his exploits and there are even places in the region named for him.
Colter reunites with Potts who agrees to become his partner on his next trading expedition. The men head into the wilderness and are attacked Blackfeet. Colter is shot in the leg but survives. The men continue their journey and encounter another group of Blackfeet. Ambushed, Potts is killed and Colter is captured. In accordance with Blackfeet tradition, Colter is given a head start to escape so the Blackfeet can pursue him. The story returns to its opening with an injured Colter racing through the wilderness with the Blackfeet on his heels.
Amazingly, despite having no supplies, Colter is able to elude the Blackfeet and begins an arduous journey back to civilization. Equipped with only his wits and a stolen blanket, he endures myriad hardships. At last, he reaches an outpost and learns he's traveled over 200 miles in eleven days. Colter returns to his life as a trapper, grateful to be alive.
Sometime later, Colter encounters Drouillard again and it's revealed Lewis killed himself because of debt. Colter announces his intention to return home and see if Sallie is waiting for him but Drouillard decides to continue with his trapping and is later killed by Blackfeet.
Colter returns home and reunites with Sallie, who has waited for him all this time. They marry and Sallie is soon pregnant but Colter becomes restless. Not long after, war with the British breaks out (The War of 1812) and Colter decides to join, prompting a fight with Sallie. Over her objections, John joins a ranger group and makes peace with his decisions before succumbing to jaundice. Back home, Sallie learns of the death and heads off with their son and her brother to start a new life. In a coda, it's revealed that Colter's name remains famed throughout the Yellowstone region and an annual race commemorates his incredible run.