The boat's passengers include a young couple whose husband is on his way to his first assignment as an Indian agent. Also aboard is a man who plans to try to bribe the new agent to help him smuggle liquor to the Indians.
A wealthy young man's marriage is in danger when an ex-girlfriend claims that he married his new wife for money. He also discovers that his father appears to be involved in the attempt to break up his marriage.
Even though Dan Simpson lost his last cargo, he refuses to give up his dream of building a general store in the West. The river pirates that made $20,000 stealing his merchandise the first time are planning to stage another robbery, in spite of Ben Frazer's precautions.
Seeking cargo for his riverboat, Captain Holden docks in the town of Hampton and discovers that Fowler, the town boss, won't allow the farmers to ship their crops. Desperate for work, Holden agrees to host the wedding of a local townsman. When Fowler's brother dies trying to kill the groom, the boss leads a lynch mob against Holden and his ship.
A woman kills her brutal husband in self-defense and flees her plantation, with the husband's ne'er-do-well brother in pursuit. She takes passage on the Enterprise and meets with an unscrupulous man who has stolen a fortune from his wife and wishes an accomplice to help him evade police pursuit.
In Natchez, the Enterprise takes on board a number of passengers one of whom is transporting a large consignment of exotic animal bound headed for a traveling circus headquartered in St. Louis. On the trip upriver, the riverboat's crew must deal with a marauding ape who can climb into passengers' rooms and steal their valuables, then disappear into hiding somewhere on the vessel.
The U.S. Army plans to commandeer The Enterprise to launch a punitive expedition against the Indians and avenge the loss of Lieutenant Devereaux and his men. Frazer tries to convince the army brass that the local Indian agent and his men are the cause of the Indian uprising.
An escaped prisoner being returned to jail is chained to the Enterprise's mast by his guard. The convict has medical training, but refuses to aid a child who been stricken with a communicable disease that puts the riverboat's passenger and crew at risk. Damage to the ship's engines prevent her from steaming upstream to a port with a doctor.
Holden agrees to ship a box full of valuable diamonds, not realizing a pickpocket has already switched the box with the real stones for worthless paste. Complicating matters are a beautiful widow, a young stowaway who wants to become a riverboat pilot.
During Texas' War of Independence, Holden agrees to ship a load of lead to Sam Houston's forces for use in fighting the Mexican army in Texas. Santa Ana's agents are determined to prevent the shipment from arriving and plan to blow up The Enterprise before it can arrive using credentials stolen from one of the Texans.
An actress charters the Enterprise to transport her and her manager to an abandoned trading post, offering Grey Holden $2000 if they can leave immediately. Although he will be forced to travel with a skeleton crew since most of his men are on shore leave, the Captain can't turn down such a generous payment. Only after the riverboat is underway does Holden learn that the woman retrieve a son from a family of river pirates who claim to have rescued the boy from Indians.
A businessman charters the Enterprise to deliver a cargo of farm machinery to thriving river port. When Frazer learns that the "machinery" is actually crates of guns and ammunition - enough to arm a military force and carve out an empire west of the Mississippi, he refuses to ship the boxes until he learns that agents are holding Grey Holden captive to assure the crew's cooperation.
Grey Holden and his riverboat are hired to deliver a cargo of guns, ammunition and troops to an army outpost on the Missouri River. When the Enterprise docks at a landing to pick up wood, Grey learns that the Sioux Indians are gathering for an attack. When Grey decides to turn back, Sergeant Carmody commandeers the vessel.