While delivering a prize bull to New Mexico, the Virginian meets a young woman, Kathy (Dolores Hart), and two older companions, whom he learns are missionaries who want to travel to Mexico to minister to the Yaqui Indians. He later learns they had hired a dishonest guide who plans to rob them so he sets off in pursuit and manages to save them. However, they refuse to give up their quest to the Yaqui's who it turns out had murdered their husbands the year before. He accompanies them on their quest and along the way finds himself falling in love with Kathy.

Judge Garth is asked by an old friend, Wade Anders (Lloyd Nolan), to take his eldest son Hank (Chris Robinson) to work as a hand at Shiloh. He wants the son to eventually take over his ranch but Hank has personal problems which make him difficult to handle, especially a hatred for Indians. At Shiloh he has run-ins with Trampas who is acting as foreman while the Virginian is away, and this conflict eventually leads to tragedy and a showdown.

After she calls for the President to bring in the army to rid the badlands of outlaws, newspaper editor Molly Wood, the Virginian's love interest, is murdered by four of those outlaws: O'Dell (Steve Ihnat), Horn (John Milford), Denver (Berkeley Harris) and their ruthless leader, Colonel Calhoun (Robert Lansing). The Virginian joins a posse but while the other posse members give up he eventually locates the villains' badlands hideout. He poses as a prison escapee, joins the gang and exacts his revenge.

Rancher Mike Tyrone (Ed Begley) purhases a ranch near Medicine Bow, and moves there with his daughter Margaret (Beverly Owen), and his two sons (Rees Vaughan and James McMullen). Tyrone tries to force surrounding ranchers to sell their spreads, eventually cutting off the water from a local river that the other ranchers use to water their stocks. However, the conflict is ended by an unexpected decision of Margaret Tyrone.

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.