Trappers lead an expedition against river pirates and Indians along the Missouri River.

In 1832, trapper Jim Deakins leaves his Kentucky home to look for work in St. Louis. En route, Jim meets Boone Claudel, a quick-fisted fugitive who has been falsely accused of a crime. Boone and Jim become fast friends, and Boone joins Jim on his journey. Soon after the two arrive in St. Louis, Boone strikes an innocent Indian crossing his path and tells Jim that he dislikes all Indians. It eventually becomes clear to Jim that Boone's prejudice against Indians stems from the poor opinion he holds of his alcoholic uncle, Zeb Calloway, who is half Indian. While searching for his uncle, Boone meets Sam Eggleston, the ill-tempered owner of the Missouri River Co., who tells Boone that Zeb owes him money for a missing delivery of whiskey. Later, Boone and Jim are thrown in jail for starting a barroom brawl with Eggleston and his men. To their astonishment, Boone and Jim discover that their cellmate is none other than Zeb. Zeb tells Jim and Boone that Eggleston and his company dislike him and that they killed his partner because as a free trader he was too much competition for the Missouri River Company. Following their release from jail, Boone and Jim decide to join Zeb on a keelboat expedition up the Missouri River and into dangerous Montana Indian territory. The head of the expedition, Jourdonnais, warns his men that they are about to embark on a 2,000-mile journey into the heart of the Blackfoot Indian territory, a region that has never been traversed by white men. To quell the trappers' fears, Jourdonnais explains that their safety will be ensured by the presence of Teal Eye, a young Indian woman, whom they will be escorting to her Blackfoot chief. Once the expedition gets underway, Zeb tells Jim and Boone that the Indians fear the white man's presence in their territory because of what they call the "grab," the white man's habit of grabbing everything in sight. Many months into the journey, the expedition, having survived the perils of white water rapids and Indian attacks, is beset upon by a group of white men, who attack their camp and abduct Teal Eye. The attackers, who are all in the employ of rival fur trader MacMasters, then try to sabotage the traders' effort to reach the Blackfoot territory by setting fire to their ship. The ship is saved just in time, and two of the saboteurs are captured by the traders and later confess to working for MacMasters. Teal Eye is eventually rescued and rejoins the expedition as it enters Blackfoot territory. Once the traders reach their destination and pick up their furs, Boone announces that he has decided to marry Teal Eye and live among the Blackfoot.