While Sime and Davey are heading for Outpost carrying freight, two bank robbers fleeing from a posse — Joe Brady and a wounded man named Tanner — hijack the stagecoach during a sandstorm.

After they take shelter from the sandstorm in the cabin of an impoverished woman named Martha Whitlock, Tanner faints from loss of blood and Brady forces Sime to remove a bullet from Tanner′s shoulder.

Leo Calloway, an embittered Confederate States Army veteran who blames a comrade named Toby Reese — who deserted him on the battlefield during the Siege of Vicksburg in the American Civil War — for the loss of his arm, holds up the stagecoach looking for Reese, but finds only Sime driving and Davey and Davey's new dog Hannibal II – a replacement for the original Hannibal, who ran away — riding inside.

Liverpool Jack, an English sailor who jumped ship along with another man in San Francisco, is heading inland as he flees a group of men who killed his companion and burned his remains.

Approaching under a flag of truce, Martin explains to the people in The Halfway House that he is a health official, that Jack was from a ship which had suffered an outbreak of the bubonic plague, that the ship had been blown up, burned, and sunk and its entire crew killed to prevent the spread of the plague, and that Jack and everyone who had come into contact with him, including everyone in The Halfway House, also had to be killed and their bodies burned to contain the disease.

During the next leg of the run, ex-Confederate States Army Captain Beaumont Butler "Shenandoah" Buell and his three accomplices hold up the stagecoach, intending to steal Duncan's money.

Not finding Duncan aboard, they order Luke to proceed to a way station, where they murder the owner and decide to hold Susan hostage after Chambers reveals her father's wealth.

After discovering that they are fleeing a private detective from Cheyenne in the Wyoming Territory named Sam Murdock, who is seeking to apprehend Deborah for kidnapping Abigail, Sime is reluctant to help them because of his responsibilities as a deputy U.S. marshal.

Davey insists that Deborah and Abigail are fleeing injustice, not justice, and that in any event they cannot leave a woman and girl alone in the wilderness, so Sime agrees to give them a free ride into Outpost in the stagecoach.

After famous singer Lily de Milo arrives in Outpost for a singing engagement and the community welcomes her, a stray bullet seriously wounds her.

To prove to himself that he did not burn down the factory, Jethro lights a candle in the timberland during the journey, igniting a large forest fire, and Luke, Sime, and Davey face the challenge of getting their passengers to safety.

The murderers eventually arrive in Outpost and threaten to shoot Davey's dog Hannibal II, culminating in a gunfight by the river.

After picking up a Scottish trapper and prospector named Sandy Campbell along the way, the stagecoach stops at The Halfway House, where ex-U.S. Army Captain Jackson Lee joins them.

Campbell drops his Scottish accent and reveals himself to be a colonel from the United States Department of War, and it becomes apparent to Sime and Luke that all of the people who have gathered at The Halfway House are interested in getting their hands on a stolen U.S. Army payroll.

When the stagecoach happens by, Griz and Cowboy take Davey and Hannibal II hostage and force Luke to put on a cavalry uniform and Sime to drive the horses.

Luke nonetheless confides in Marshall Strickland, who convinces him that Doty plans to kill everyone anyway and that the only way to save the hostages is to return to the way station with a large posse.

With Sime at the reins and Davey along for the ride, the stagecoach heads eastward carrying Colonel Sam Carlin, a U.S. Army colonel suffering from post-traumatic stress disorder who is known to Mexicans as El Carnicero ("The Butcher") for his harsh rule in California, where he is known for frequently hanging Spanish-speaking people; Carlin is headed to Washington, D.C., to answer charges that his use of the death penalty has been excessive.

After suffering a wound in a dispute with Indians, U.S. Army soldier Julian Tibbs crashes his wagon — which is carrying $190,000 in gold — and passes out across the road.

Although he killed in self-defense, he is wanted for murder, and he flees to Outpost to seek out the Reverend Jim Hallett, an old friend of his from the Union Army who he had helped survive imprisonment in Andersonville Prison during the American Civil War.

When he arrives there, he finds that his brother Sam is on the run from the law in the area after the U.S. marshal in Tucson jumped to conclusions and charged him with a robbery and murder he did not commit.

Soames is scheduled to arrive by buckboard the following day, and Harney's plan is to kill him and plant the stolen calf with his body to make it look like he was a cattle rustler.

Luke, Sime, and Davey are pioneering a new stagecoach route from Outpost to the U.S. Army post at Fort Tremaine, with a stop at The Halfway House.

On the first trip on the new route, they are carrying a large payroll for the fort, and among their passengers is a man calling himself Stokes, but Luke eventually recognizes him as Rupe Larned, who had killed a stagecoach-driver friend of his in Kansas.

While Davey drives the stagecoach to The Halfway House with Angela aboard, Luke and Sime decide to herd the late Manolo's sheep.

Hogan and two of his men attack them, and Luke and Sime employ the tactical skills they learned as soldiers during the American Civil War in the gun battle that follows.

Luke and Davey head out on the stagecoach with the disgraced marshal of Timberline riding shotgun and carrying three passengers – a conman who poses as a preacher to get money from the gullible, a gambler run out of town after he was caught cheating, and an arrogant snob from the East.

A gang of con men led by Hollis Collier arrives in Outpost intending to swindle the townspeople by getting them to invest in a fake gold mine.

Five United States Army soldiers led by two men about to face a firing squad break out of the guardhouse of a fort, murdering guards as they do, and head for Canada.

Luke and Sime believe that the gang will murder them after reaching Canada, and they try to sow dissension among their captors and slow down the trip to give a pursuing Army force time to catch up with the stagecoach.

Luke falls for Jenny Forbes, a saloon girl in Colorado, helps her escape from her cruel boss, Mingo, by stowing her away in his stagecoach, and gets her a job as a cook at The Halfway House.