While out looking for water Coop and Charlie are stopped by a gang of five, including two women, who are on the run after robbing a bank and killing three lawmen. The leader of the gang shoots Charlie after tying him up, and they take Coop to lead them through a mountain pass to get to California.
Hale finds his old flame Chottsie Gubenheimer (played by John McIntire's real-life wife Jeanette Nolan) working in a gambling house and in an argument with the owner, so he asks her to come with him and join the wagon train. He comes to realize that he's getting more problems than he bargained for.
Wanda Snow has several times seen events before they have happened, causing several people on the wagon train to accuse her of being a witch. A medicine show peddler/magician gets the idea to use her in his act, but this creates friction between him and his devious partner.
Coop and Charlie ride into a small village for supplies finding it deserted. There is an Indian who stays hidden and later three men and a woman ride into town. They have been looking for the woman's father in a cave filled with bats.
The wagon train comes across old Jamison Hershey and Herman, his 3000 pound Belgian horse. The old man has made it safely through hostile Indian territory because the tribes are so in awe of his horse. Hershey and Herman are invited to ride with the train, though it becomes apparent that Herman is not able to travel very fast and may hold back the entire group.
Don Brooke is desperate for money for his pregnant wife Bonnie, who's condition is too delicate for the long trip without more medical care so he seeks a bank loan. When he sees an opportunity at the bank, it leads to tragedy.
Teacher Mary Lee McIntosh refuses to pay what she feels is an excessive fee to join the wagon train, so she decides instead to follow behind it in her wagon alone, and refuses help from Hale. But after her wagon overturns, things change.
Tough and headstrong female ferryboat captain Samantha Stewart is asked by her son Johnny and his bride to accompany them on the wagon train to California, where they will board a ship for a Pacific voyage. But actually, Johnny is not telling his proud mother that her doctor has told him that she must stay with a dry climate on land or she will die.
Despite the advice of some Coop decides to visit former girlfriend Eloise Blee, but finds Eloise gone, and instead winds up being talked into posing as her twin sister Betsy's missing husband and father of her baby daughter.
Barnaby is forced to shot and kill a boy his own age who took a woman and her daughters hostage. He is cleared of any wrongdoing but cannot shake the blood he feels is on his hands plus the judge wants him to inform the boy's mother.
A white renegade rides into the wagon train camp with an Indian girl tied to a rope and forced to walk without food or water. He says that he is bringing her back to the tribe where she will be tortured and killed for killing the chief's son. Hawks, in charge of a smaller group until Hale and Coop meet them with the rest of the train, decides to forcibly take the girl from her sadistic captor and keep her with his group, even knowing that this may lead to an attack from the chief's tribe.
Coop tells Bill the story of the Earp brothers and the Silver Lady, a woman who was encased in a coffin of sliver coins that melted around her after the stagecoach she was riding on and guarded by Morgan Earp had an accident and burned.
The series' final episode begins and ends with the two characters who stayed with it from beginning to end, as Charlie tells Hawks about his earlier days working for trading post operator Jarbo Pierce. Jarbo, once a wild, hard-drinking man, had become a minister, though he could still take on any man who tried to fight him. When his younger brother Adam arrived at the post Jarbo found himself at odds with him as Adam preferred the wilder ways of life and didn't understand Jarbo's concerns for the Indians he traded with, and began working with a man who wanted to use ...