A former law man and now hired gun, Emmett Ryker (Clu Gulager), heads to Medicine Bow at the request of Hagen (Leslie Nielsen). Hagen holds a mortgage on the ranch of Hale (Russ Conway), a friend of Judge Garth, and wants to run the rancher off the property. Being a man of some morals, Ryker refuses to become involved but when Hale is killed he is suspected of the crime. Ryker becomes friends with Trampas and agrees to help Hale's daughter Janet (Anne Helm) bring the guilty parties to justice

Carl Hendricks (Victor Jory), with his son Arnie (Chris Robinson) and daughter Jenny (Katharine Ross), buys a local ranch. Trampas is embarrassed when he tries to get Jenny to dance at a local gathering without realizing she has a club foot. He apologizes, they become friends, and he begins setting up Jenny with his shy blacksmith friend Wally (Larry Pennell). Carl is subsequently murdered and Trampas is a suspect although he had no motive. It is left up to Deputy Emmett Ryker to solve the crime.

A wild stallion escapes its owner, John Slaughter (Don ""Red"" Barry), killing a handler in the process. The animal injures itself and is found by Randy Benton who takes him to the nearby ranch of alcoholic horse trainer Charlie Orwell (Robert Culp) who nurses it back to health. Most believe the horse bad and wish to have it destroyed but Randy gets Charlie to help him save the animal and with the help of Jodie Wingate (Jenna Engstrom), they save Charlie too.

Posing as a newspaper man, James Templeton (Steve Forrest) comes to Medicine Bow to interview Judge Garth who is a leading candidate for territorial senator. Betsy Garth is smitten with James who is just about perfect in everything he does whether it is riding or shooting and this makes Trampas suspicious. His suspicions turn out to be well-grounded.

Felicity Andrews (Katherine Crawford), the new Medicine Bow school teacher, lives with her older sister Kate (Mariette Hartley) and grandfather Jonah (Carl Benton Reid). Everyone raves about her and the Shiloh hands, including Steve Hill, are all smitten but Felicity's heart is won by the Virginian who proposes to her. However, Felicity's family protects some secrets which eventually brings an end to the Virginian's marriage plans.

Samantha Frye (Barbara Eden), who has been fired from many newspapers for her exaggerated stories, arrives in Medicine Bow where she begins working for the newspaper and becomes courted by the Virginian and Emmett Ryker. She begins a series of articles for the ""Police Gazette"" about a legendary but supposed dead outlaw called the Brazos Kid and her hints he is still alive bring a bounty hunter, a detective and a man seeking revenge on the outlaw, to Medicine Bow. Complicating matters even more are the facts the Kid is really alive and living incognito nearby and that the Virginian is his friend and is aware of his identity. Because Samantha's descriptions of the Kid resemble the Virginian, the Shiloh foreman becomes the target of the Kid's pursuers.

Millionaire Paul Leland (Linden Chiles) treats everyone like dirt and ends up in the desert after getting shoved off a train by a disgruntled employee. He is found and taken on by the Virginian and Shiloh crew who are driving a herd of cattle to Seattle. Leland has several run-ins with the crew as well as former employees met along the way but in the end becomes a better man for his tribulations.

At the Medicine Bow orphanage Toby Shea (Kurt Russell) makes up stories about his great father which none of the other boys believe, so he befriends Trampas and tells the other boys Trampas is his father. His real father, Jim Shea (Rory Calhoun), who has been released from prison, tries to find his son but is trailed by two former partners in crime seeking some lost loot. Jim Shea becomes a hand at Shiloh Ranch and manages to keep his identity secret until his former partners and his past catch up with him.

Steve Hill is asked to go under cover by a US Marshall (Don Collier) by renewing his relationship with a former girlfriend, Jane Carlisle (Ruta Lee),who is a new dance hall girl at the Medicine Bow saloon. The Marshall suspects Jane is part of a notorious robbery gang out to steal gold destined to pay for Indian land. Steve reluctantly agrees to do so and to gain the gang's confidence begins to act irresponsibly much to the chagrin of the Virginian and Shiloh hands who are unaware of his task. In the end Steve must face the robbery gang and its ruthless leader (Mark Richman) and his fate is in the hands of Jane.

An old friend of Judge Garth named Charlie Ryan (Leif Erickson) revives the low grade silver Gloria Mine with help from his mining college-trained son Craig (Peter Brown) and a new partner Whit Parsons (Whit Bissell). They fall behind in their payments and may not make quotas specified in their contracts. A desperate Craig begins to alienate the locals including Judge Garth with his tactics to save the mine operations. Things come to a head when local cattle begin to die and contaminated mine water is suspected. This leads to conflict not only between the local ranchers and miners but eventually to conflict between Charlie, his son, and especially their business partner, Whit, who seemingly will stop at nothing to make the mine a success.

Victoria Greenley (Anne Francis) comes to Medicine Bow to set up a law practice but encounters resistance from those who do not think law a suitable profession for a woman. Although initially reluctant, the Virginian gets Victoria to represent him in a court dispute with a saddle-maker. She is successful and romance brews between the two. However, they soon find themselves on opposite sides when Victoria agrees to defend some men accused of trespassing on Shiloh land.

Widower Sam Horn (John Lupton) comes into conflict with the railway headed by Colonel John Briscoe (Edward Binns). Part of his land had been expropriated as a railway right of way and the compensation was based on much outmoded land values. The Colonel is also having conflicts with his son Scott (Buck Taylor) over an old girlfriend of Buck's called Peg Dineen (Laurel Goodwin) who also happens to be in town. Peg is a supposed widow with a young child and Sam Horn is smitten with her. When Buck is shot, Sam is put on trial for murder although he claims it was self-defense. In the courtroom it is up to Judge Garth to defend and save Sam Horn by uncovering the tangled and hidden motives behind the events.

French-accented portrait painter Charles Boulanger (John Gavin) says goodbye to Betsy Garth and Maggie Mencken (Vera Miles) who have been visiting Chicago. Maggie is a good friend of Judge Garth and the Judge is the executor of her late husband's estate. Charles accent is phony and he is wanted by hoods trying to collect a gambling debt so he escapes to Medicine Bow by saying he will paint Maggie's portrait. At Maggie's house Charles discovers an important art work purchased by her late husband and while romancing Maggie, makes plans for faking the painting and selling the original to pay off his debts. However, two things stand in his way: his growing affection for Maggie, and Judge Garth, who suspects Charles is not what he seems.

Ryker invites the man who raised him to come to Medicine Bow after being released from 10 years in prison. When Ryker finds Abe has invited his family to join him, he knows there are problems as Shiloh makes a record sized cattle shipment.

Trouble comes to Medicine Bow in the form of a number of settlers who camp on land they say has been promised to them but that Judge Garth and others traditionally have leased from the government for grazing cattle. The land settlement has been promoted by Congressman Matt Cosgrove (James Dunn) who had read law with the Judge 30 years before. The Judge knows the soil is no good for farming but is told government reports support the reverse. While the Judge and Cosgrove are at odds, Cosgrove's nephew, Army Lt. David O'Mara (Martin West), and Betsy Garth find each other more to their liking.

A landslide blocks the pass needed to drive the Shiloh cattle to the rail line. The only alternative route would have to cross the property of Junius Antlow (Tom Tully), an arch enemy of Judge Garth, and Antlow refuses permission to use that route. The Judge hires Big Jim Lafferty (Leo Gordon), foreman of a crew of Chinese coolies, to clear a way through the blocked pass. Amongst the Chinese, disguised as a man, is a girl, Kam Ho (Cely Carrillo) who falls in love with the Virginian even though she is promised in marriage to one of the other workers named Chang (Kam Tong). Junius Antlow attempts to sabotage the work, hoping the cattle will starve, and in the process some of the Chinese labourers are killed and others wounded. His actions bring him into conflict not only with the Judge but also with his own son, Chris (Tom Simcox), and tragedy results.

The Virginian hires some workers to help drive some cattle to Shiloh from Cheyenne, among whom is an easy going and timid hand who reads Shakespeare named Eddie Laredo (Fabian). Eddie accepts a full-time job at Shiloh but he is razzed by locals, including the unsavoury Bojo Sanders (Rayford Barnes) and saloon girl Molly Weems (Elizabeth McRae), because he likes literature. Bojo is murdered and Molly testifies that Eddie killed Bojo but because of her unsavoury reputation the charges are dismissed. Molly Weems is also killed and Trampas sees Eddie riding away from the scene. It looks like Eddie is guilty and will face the death penalty despite the efforts of Judge Garth to defend him.

Betsy Garth investigates rumours of wild broncos in the mountains and while there she encounters a young man, Clint (Andrew Prine) and his father Martin (Forrest Tucker) living in an isolated cabin. Clint gets Betsy to promise not to reveal their presence but when Betsy is bitten by a rattlesnake he is forced to take her to Dr. Spaulding (John Bryant) in Medicine Bow, thereby saving her life and earning the Virginian's gratitude. However, Martin is a wanted man and Emmett Ryker is on his trail. Betsy must choose between her growing friendship with, and promises to, Clint and revealing the hideout to the law.

Emmett Ryker learns that a man named McMasters, who had killed his good friends, a rancher and his daughter, two years before, was one of six men supposedly killed by Indians. Believing the man still alive, and seeking revenge, he accompanies a young woman, Lucille Carver (Sheilah Wells), whose father was also reported as among those killed, to the massacre site at Cripple Creek. The trail eventually leads him to Deadwood where he suspects a man who has made a gold strike, and may be Lucille's father, is McMasters.

A man dies due to a gunshot wound but not before he reveals to his sweetheart, Clara Malone (Shirley Knight), that robbery money is hidden near Medicine Bow. Faking suicide to escape the rest of the robbery gang, Clara takes the stage to Medicine Bow along with one other passenger, the Virginian. In a stage accident she is injured and the Virginian takes her to Shiloh Ranch to be nursed by Betsy. Suffering from amnesia, Clara can not recall her past and she and the Virginian begin a romance. However, her past catches up with her when the robbery gang discovers she is still alive.

Trampas is in Albuquerque to pick up some money on behalf of the cattlemen's association. He encounters and is robbed of some of the money by Charity (Kathryn Hays). She was in love with a man, Byron Prescott (Jerome Courtland), who was forced to jilt her by his wealthy family. Charity is trying to get to Rancho Valdez to sell a ruby ring, a family heirloom which had been given to her by Byron. Although Trampas catches up with Charity, she in turn has been robbed by a local guide, Judd (Warren Oates). They set out after Judd, tailed not only by Byron Prescott, but also by Emmett Ryker who has come looking for the overdue Trampas.

The Virginian makes the acquaintance of a young man, Mark Shannon (Richard Beymer), who along with his sister (Diana Lynn) and her love interest, trail boss Jack Slauson (Myron Healey), is taking a cattle herd to the army. When near Medicine Bow it is learned the Shannon herd could be carrying Spanish fever. Those cattle are largely immune but the local cattle are not. The local ranchers, with the Virginian acting as their delegate, try to get the herd to bypass the Medicine Bow area. By taking another, but more direct, route, the herd would avoid infecting the local cattle. However,there would be substantial losses to the Shannon herd because of a drought affecting the other route. Mark refuses and this leads to a showdown not only with the Virginian and Medicine Bow ranchers but also with Slauson.

Emmett Ryker's good friend, storekeeper John Conway (Jack Warden), is to marry a woman he met in San Francisco and has known for only a very short time, Rita Boland (Marilyn Erskine). When Rita comes to Medicine Bow, her relationship with John becomes strained because of her seeming unwillingness to consider having children. She turns to the bottle and it is clear she is haunted by some event in her past. Meanwhile, Emmett's past also threatens to catch up with him as two Garr brothers (John Milford and James Beck) whom he had sent to jail for a robbery attempt, and whose third brother he had killed in that same attempt, come seeking revenge. The two disconnected stories become intertwined, and then resolved, in a fateful showdown.

In Cobb's Run, Kansas, while waiting for the Virginian, Randy Benton is framed for a $50,000 payroll robbery. His defence, that the legendary but aging town marshall, Floyd Buckman (Ford Rainey), had inadvertently allowed the robbers into the bank, is scoffed at by the locals. As a result, Randy is sentenced to be hanged. The Virginian tries to track down the the real robbers to prove Randy's innocence and in desperation even breaks Randy out of jail. In the end however, Randy's salvation is in the hands of the legendary lawman.

Local ranchers are upset with the lumbering of Charles Daniels (Arch Johnson) which they believe will destroy a valuable watershed area and ruin grazing land. Daniels refuses to listen to their entreaties as delivered by the Virginian and Emmett Ryker has to try and keep the peace despite the growing tension. Complicating matters is a budding relationship between Daniels' daughter Katie (Joan Freeman) and the son of one of the local ranchers opposed to the logging, Dave Ferguson (Martin Milner). This relationship is frowned upon not only by Daniels but also by Daniels' foreman, Paul Rogers (William Smith). When Rogers is killed accidentally by Ferguson, Daniels believes it murder and seeks revenge.