Matt Denning (Robert Lansing), a good friend of Emmett Ryker's, believes his younger brother Will (Andrew Prine) innocent of a crime and breaks him out of a military jail where he is awaiting execution, accidentally killing a guard in the process. Along with Matt's wife (Jan Shepard) and son (Kurt Russell), they escape into an area where many Sioux Indians are out for blood, and are trailed by Ryker, army Sgt. Cohane (Myron Healey) and three soldiers. They find the escapees but the party is attacked by the Sioux. Will is killed, confessing as he dies that he was guilty as charged and leading Matt to realize all has been for nothing. Despite the fact the guard's death was clearly an accident, and the fact Emmett and Cohane testify on his behalf, Matt is found guilty and Emmett is forced to uphold the law and turn Matt over to the Sheriff who will escort him to prison.

An Australian, Adam Tercell (John Anderson), has bought a local ranch and plans to graze sheep on open range, a strategy which would destroy it as grazing land for cattle, so the locals want to negotiate an area set aside for sheep. However, Tercell's bullying son, Abel (Jon Locke), refuses and even stockwhips a local rancher (Edward Faulkner) which brings him into conflict with the Virginian. Abel tries to bullwhip the Virginian and falls and is accidentally killed when he hits his head on a rock. Adam Tercell arrives in Medicine Bow and tries to get the Virginian charged with murder but is unsuccessful and things become complicated when Tercell's daughter Reagen (Maura McGivney) begins to fall in love with the Virginian. Events continue to escalate and eventually lead to a fateful confrontation between Adam Tercell, his estranged daughter, and the local ranchers.

After release from prison, Bert Kramer (Bruce Dern) comes to Medicine Bow to find his estranged wife who is the new school teacher, Martha Perry (Susan Oliver). A Shiloh hand, Rafe Simmons (Albert Salmi), tells the Virginian he is quitting. He goes to town, get a job in the harness shop and gets Martha to teach him to read. Bert Kramer arrives in town and is spotted by Emmett Ryker who recognizes him as a hired gun. Rumours are spread that Rafe and the schoolteacher are having an affair. A local barber, Cal Beeson (Harry Townes), who has had a run in with Rafe, and Bert Kramer plot together to ambush the harness shop worker. However, Rafe manages to get the upper hand. In a struggle over a gun, Bert is killed but Rafe is cleared by the actions of the Virginian and Martha who get Beeson's young son to own up to the plot.

Trampas becomes discouraged with being a ranch hand and sets off with an old friend, Luke Milford (William Shatner), to Deadwood City in the Dakotas where gold strikes are reported. They learn that most of the gold is off limits in Sioux territory but they meet and help a man named Finley (Strother Martin) who claims to have a gold strike outside of Indian land and who agrees to cut them in if they will stake him for equipment. They do strike gold but it turns out it is on Indian land. Trampas runs into trouble not only with the Sioux but inevitably ends up in a showdown with Luke who has become fixated on finding and retaining the gold.

A destitute former Minister, David Henderson (Glenn Corbett), who has had a crisis of faith, comes to Medicine Bow just as a dispute breaks out at a local mine over safety issues. Emmett Ryker entreaties Judge Garth to try and find a solution to the problem. When an accident occurs at the mine David's assists in a rescue attempt but hurts his leg. He is taken to Shiloh where Betsy Garth nurses him and they become romantically involved. David's actions gain him the respect of the miners, he becomes their leader, and he calls a strike over the working conditions. Despite an attempt to intimidate the miners by importing scab labour, with Judge Garth's help the owners and miners manage to reach an agreement. David rediscovers his calling and asks Betsy to marry him. They are married at Shiloh Ranch and head off to start a new life at a parish David has been assigned in Pennsylvania.

Emmett Ryker is amongst a group of stagecoach passengers and crew waylaid by and trapped in an isolated cabin by a group of Mexicans from a small cross-border town. The Mexicans want one of the passengers, a cowboy named Wylie (Earl Holliman), for murdering a woman but Emmett believes Wylie should be turned over to the American authorities for a proper hearing. A siege and gun battle ensues but in the end, the Virginian and Trampas, who are waiting for Emmett in a nearby town, come to the rescue of their missing friend.

Judge Garth's niece Jennifer comes to live with him at Shiloh after her parents are killed in an accident. However, she is uncomfortable with her uncle who disapproved of her father. A young man she met seems to help but he has a past.

Ben Justin takes over a ranch next to Shiloh. He has had a string of bad luck including the death of his first wife. His son wants to help him but Ben keeps him and his wife Mary at arms length out of fear they will see the real Ben.

While returning to Shiloh Trampas injures his horse saving a man with a runaway team. He is forced to stay a few days in a small town with the man as an old friend arrives to force the town to sign over its gambling rights to him.

On a trip to Mexico with Trampas to pick up six palominos The Virginian becomes sick. He is forced to stay at a lonely saloon and inn tended by the girl friend of a local outlaw. As he recovers she decides she would prefer life with him.

Widower Stavros Karas has agreed with a friend in Greece to marry his daughter. He told his friend he had a nice place but in reality he has little and needs water from his neighbor whose son falls for his young and beautiful bride.

Two tramps kill the wife of Ev Clinchy provoking the ire of Ev and his friend Hezekiah who want to lynch them. The sheriff keeps them at bay but when he is killed it is up to Ryker to protect the men against his close friends for trial.

A dying man clears a man sent to prison but the Governor and the railroad still believe he is guilty. He is paroled but still hounded by a railroad agent. When he is suspected of a second robbery, Ryker is not sure all is as it seems.

A respected but retired Medicine Bow lawman is trying to make a living for him and his daughter on a farm but the bank is about to foreclose. A man involved in robbing a gold shipment offers him gold for hiding him out.

A notorious Civil War criminal defended by Garth arrives in Medicine Bow to join his family. He expects payment from Garth who he believes profited from his case but Garth wants nothing to do with the man but Jennifer befriends the family.

Trampas and Randy are sent to pickup horses from a rich man illegally evicting people from their property who don't believe in fighting back. Trampas stays as he takes an interest in the leader's daughter who doesn't agree with her father.

The Virginian's friend Benjy is convicted of a murder he swears he didn't commit. A mountain man may be able to clear him but a search doesn't find him. The Virginian decides to follow some clues putting himself and the witness in danger.

A man and his two adult kids broke and hungry end up at Shiloh when their wagon breaks down. They are grifters but the old man decides to stay at Shiloh. The kids soon like it but don't feel they fit in not knowing their dad is scheming.

Jennifer learns by accident a hand has a learning challenged sister who is near adulthood but hidden from society. She convinces the parents to let her help the girl but the girl's involvement with a bank robber complicates the problem.

Morgan Starr takes over for Judge Garth running Shiloh. His hardnosed demeanor doesn't sit well with anyone on or off the ranch. His introduction is made harder by a locust plague when Starr decides to stay and fight them rather than move the cattle.

As Ryker leaves town for a few days, a group of men known as Metis arrive in Medicine Bow. They are a rough group but want no trouble. However, the people are afraid of trouble which comes as Starr tries to stop it - from themselves.

Trampas becomes knight errant when he takes on two children trying to reach their mother in Laramie. They are being chased by a group of outlaws who want to return them to Mexico. A woman he adds on the way makes it feel like a family.

Morgan Starr and Randy Benton travel to sell a herd of cattle to an Indian agent to feed the Dakota, but find themselves on a journey of loss and finding, resulting in a change for many lives but especially for Randy.

After 35 years in prison Tom Brant returns to Medicine Bow. A newspaper reporter's story about him stirs the interest of people who had various connections to him. People swarm to him for different reasons including the money he hid.

Randy goes to Montana to pick up a mare and see his childhood friend Georgie Sam with whom he plans to start a horse ranch. Randy is introduced to a rancher's daughter who he falls in love with but her family is suddenly in a crisis.

The Virginian attempt to recover money Shiloh spent on diseased cattle becomes embroiled in a blackmail attempt and finally murder. A pretty woman is involved who was just released from prison for murder and is the talk of Medicine Bow.

Starr with Trampas agrees to go to Mexico to check the security of a town where A US Senator and a Mexican Governor plan to sign a treat. All looks okay so Trampas leaves but Starr soon finds he is in the middle of an assassination plot.

Randy's family visits from the hills of Bald Knob to protect him from a Claiborne who has been released from prison. Randy's testimony helped send him to prison. His daughter a childhood friend of Randy complicates his desire for revenge.

The Virginian takes responsibility for a young man he injured when the man vandalized Medicine Bow. The man is intelligent but from a poor background. His girlfriend's wealthy father wants him gone to protect his daughter who is in love.