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.
A pretty stowaway convinces Grey Holden and his crew to rescue a group of teachers who are held as political prisoners on an island off the coast of Mexico for advocating democracy. Grey must not only adapt his riverboat to sail across 40 miles of open sea, but create a plan to overcome the soldiers guarding the Americans.
The Enterprise is hijacked by the captain of a riverboat that sank a month earlier, leaving Captain Holden and his men stranded on shore. Holden and Fraser are determined to recapture their ship and they and their crew set off on a cross-country shortcut through Indian territory to head her off.
A woman with a load of unstable, experimental, gunpowder connives to draw Holden and his men into a barroom brawl and then agrees to bail out the entire crew from jail if the captain will agree to ship her volatile cargo to her father's diamond mine.
A group of Cajuns hijack part of the Enterprise's cargo while it makes a stop for wood. Two crewmen are killed during the incident, not by the Cajuns, but by a group led by an unscrupulous man who wants to use the Cajuns' remote island for himself as a base for attacking boats.
A schooner wrecks on an uncharted reef near the Florida coast and the Enterprise and her crew rescue the only two survivors. The woman who was pulled from the wreck tells Captain Holden that her dowry, a fortune in pearls, lies just below the surface in the wrecked ship. The crew tries to retrieve the chest before a gang of salvage pirates can steal the pearls.
A wealthy but inexperience party of pioneers hire Captain Holden to transport them to Independence, Missouri, so they can join a wagon train for California. One of the group's organizers connives with river pirates to hijack the riverboat and rob the party before they can reach their destination.
A falling out among thieves occurs when a bank robber refuses to reveal to his fellow gang members where he hid the loot. His former partners kill him, but not before the dead thief's nephew flees with a map that shows where the money is hidden. When the Enterprise runs over the boy's raft, its crew manages to rescue him, but the youngster soon jumps ship with both the bank robbers and Grey Holden in pursuit.
Charged with building an canal that would shorten the river voyage and avoid rapids, Captain Holden runs into murderous opposition from the freight and stagecoach line that hauls cargo and passengers along the proposed route.
While Holden is away from the riverboat seeking business, The Enterprise, under temporary command of Brad Turner, stops at a landing for a cargo of fur pelts and find the proprietors dead with arrows stuck in their backs. Turner and several crew members ride into town to find their cargo and find the settlement preparing for an Indian attack.
In the absence of Captain Holden, Captain Brad Turner takes a cargo of military supplies to an outpost on the Little Missouri River - in the middle of Sioux country and must use the cannon he is delivering to disperse an Indian attack. He discovers the once peaceful Indians have been driven to the warpath by the actions of the fort's commander - a martinet who commandeers "The Enterprize" and its crew to fight the Sioux.
The crew finds three recent graves at a town they had planned to dock in. They also find residents of a nearby town want to kill anyone who came in contact with the three dead men. Captain Holden then meets a woman doctor who informs him that the men died of bubonic plague.
Based on a statement allegedly made by a dying man, a lynch mob forces two passengers to leave the enterprise and face murder charges before a kangaroo court. Clay Holden doesn't cotton to extra-legal methods, especially since legally constituted authority exists. He also believes that the damning testimony presented at the trial was perjured.
Needing a supply of wood, Clay Holden docks his riverboat to a small town only to find no one will sell him any. Upon further investigation, he discovers the town is being run by a gang of hooded outlaws who collect protection money from businesses and threaten all strangers who refuse to leave with violence and death.
A U.S. Army detachment is ordered to remove the Cherokee Indians from the ancestral homeland and the Enterprise is commandeered to transport the tribe to its new reservation. Gray Holden is furious because he knows the Cherokees are peaceful and law-abiding. Worse, he is close friends with many of their leaders and resents being the agent of their maltreatment.
While sailing down the Mississippi in a heavy storm, the Enterprise strikes a log that rips a hole in her side. The only way Holden can raise the money to repair her is rent her to another riverboat pilot who promptly double-crosses him by turning his vessel into a floating casino.