Ex-Marshal Bob Stuart and his new wife are among three wagons joining Chris Hale's wagon train. Scout Cooper Smith is assigned to escort the new wagons to join up with the main train but there is blood, bad blood, between the scout and the ex-lawman. Entering the mix are old friends from Cooper Smith's past who also have an ax to grind against Bob Stuart. Coop soon becomes caught in between the man he was and the man he's become as his friends set out to destroy Bob Stuart and anyone who gets in the way.
Hide hunters, hunters who kill buffalo for their hides only, have temporarily joined up with the wagon train. One of their number, Gib Ryker, is a sociopath who enjoys antagonizing young Barnaby West. With the train desperately needing fresh meat, Cooper Smith, along with Barnaby, sets off with the hide hunters to look for buffalo. Along the way Gib continues to bait Barnaby, much to Coop's dismay until Barnaby is forced to defend himself, with disastrous results. Now Barnaby has to face Gib's brother Zach, who's out for revenge.
John Gilliam is on the run from the law. Shot while trying to evade a posse, he is found by Abigail, an angry young orphan girl from the wagon train. Abigail wants desperately to be adopted, but no one will take her. Abigail takes a shine to John, but he is a bitter man who wants nothing to do with the young girl. Slowly Abigail begins to get under John's skin and into his cold heart. But Abigail hides a terrible secret that will forever change the surly outlaw.
Bill accompanies Barnaby to Sam Race's tent city of "entertainers", where a girl from the train that Barnaby likes has taken a job, not as a singer, as she had thought, but as a saloon girl. Bill hopes to keep Barnaby out of trouble with the gambling and con games Race runs, but trouble and humiliation is just what they both find.
Cooper Smith is on his way to the town of Washburn to pick up long awaited mail for the wagon train when he stumbles upon a stagecoach robbery in progress. The very proper Miss Barbara Lindquist is on her way to meet her fiancé, mistakes Coop for one of the robbers and ends up forcing him to help her. Further misadventures see Coop wounded and both he and Barbara struggling to get to back to the wagon train for help. Believing his wound will end his days as a scout, Coop finds himself falling in love with Barbara and she with him. But will their love stand the test ...
Brian Conlin walks into Hale's camp, delirious and dehydrated. After he recovers, he leads Coop to his group of Irish immigrants, whose wagons have broken down, and Hale invites them to join the wagon train. However, having been repeatedly turned away from place after place, most members of Conlin's group are slow to trust anyone or accept help.
Coop finds a young half-Indian woman wandering alone in the wilderness. He brings her to the wagon train, where Hale discovers she is a survivor of a tribe totally massacred ten years earlier. Coop begins to fall in love with the young woman, who gives her name as Leoni. But then a sheriff comes to the train and claims Leoni is Alice Whitetree, and that she has killed two people.
Hale is unable to take every wagon on the next phase and has to delay some of the train members. One whom he must leave behind is Ben Campbell, an ex-convict who is being hunted by his escaped former partner, who believes Ben turned him in to the law. Others on the train include a woman claiming to be meeting her soldier husband at a fort, an old man hiding his heart condition from his wife, and two boys running away from their abusive guardian.
Spoiled Nancy Styles, who claims to be the daughter of the owner of the company that owns the wagon train, is determined to get to Denver even though Hale has made it clear he plans to bypass the city. After paying back the young couple she was riding with by trying to steal the husband, she sets her sights on gullible young Barnaby, who is falling for her, and talks him into running away with her.
A blind man called Sangre has joined the wagon train along with his guide. He is actually Coop's boyhood blood brother Richard Bloodgood, and he openly states his plan to kill Coop. Coop gets very hostile and refuses to discuss it whenever Charlie or Barnaby ask the reason Richard wants to kill him, but they know it has to do with the death of a beautiful woman long ago.
With Hawks ill and Comanches threatening to attack, an Army troop meets up with the wagon train. The Indians appear to greatly outnumber the soldiers, so to give the train hope the troop's lieutenant falsely tells Hale and Coop that there is also a relief column headed their way. Complicating matters even more, a sergeant from the troop recognizes Clay Shelby, a young man on the wagon train traveling with his pregnant wife, as a deserter from back in the Civil War whom he blames for the death of his brother.
Charlie has finally found someone else who shares his dream of man being able to fly, henpecked inventor Hector Heatherton, who has been working on an idea for building a flying machine. Unfortunately, Hector's wife takes his dream even less seriously than all the others on the train, and he has to try to build his machine when she's not looking.
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 find a town totally deserted except for one old Indian, and four white residents who later return. They learn that the town was deserted because of a plague of bats unleashed from a cave nearby, where a professor, now missing, went searching for a treasure left behind by Spanish priests. The seven people decide to all go back to the cave to search again for the professor and the treasure, despite the bats, and the distrust one of the men has for the old Indian guiding them.
The wagon train comes across old Jamison Hershey and Herman, his 3000 pound Clydesdale. 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. When he sees an opportunity at the bank, it leads to tragedy.
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, she does accept help from crafty itinerant photographer/peddler Dan Delaney, and together they have to go through hostile Indian territory.
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.
Charlie Wooster and Barnaby West have the task of escorting Dr. Katy Piper and her daughters to join up with the Chris Hale wagon train. Barnaby is forced to shoot a masked bandit who has hijacked the Piper wagon and ends up killing the bandit. The bandit turns out to be a teenage boy, and though Barnaby is cleared of any wrong doing, he carries the guilt of the killing and the judge tasks him with telling the boy's mother of the death. His guilt is manifested in the stigma of a constantly bleeding gun hand, though there is no physical wound. Barnaby ultimately quits ...
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.
After coming upon the apparent remains of a stagecoach, Coop tells Hawks the story of the Earp brothers and The Silver Lady, a woman who died in a fiery stagecoach wreck with $20,000 in silver coins melted around her. First assuming her to be singer Anne Reed, a townsman in gave her an elaborate burial service, but then Anne Reed arrived very much alive, and revealed that the real Silver Lady was a saloon girl. The Earps and Doc Holliday investigate who attempted to hold up the stage and caused the accident. And yes, it's not a misprint, Michael Burns is really ...
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 ...