Horror mounts when a flu epidemic attacks Colorado Springs. Dr. Mike must attend the sick townspeople and protect others from getting the deadly disease. But being a lady doctor has people questioning whether she can handle the fatal epidemic.

Mike's estranged mother (Jane Wyman) visits, but she and Mike are still miles apart. Meanwhile, Robert E is injured in a fire.

A gunslinger (Johnny Cash) arrives looking for a quiet town in which to hang 'em up, but Colorado Springs is itching to lynch an immigrant (Christopher Keene Kelly) for cattle rustling to feed his starving family.

A bitter Loren, who blames Sully for his daughter's death, tries to repossess Dr. Mike's cabin when he learns he still owns the deed.

As Dr. Quinn is trying to persuade the townspeople that smallpox vaccinations are necessary, the father of Brain, Colleen, and Matthew arrives.

When several townspeople come down with mercury poisoning, Dr. Mike forces a reluctant Sully to guide her to the high mountain stream which may be the source of the problem. The trek is difficult for her, but she ultimately earns Sully's respect and gratitude after saving his life twice despite a broken wrist. Just as they confirm that the water is being polluted by a local mine owner whose mining process is dumping mercury into the stream, they are captured by his men. In the interim, worried townsfolk send out an inept posse to try to locate Sully and Dr. Mike. Olive backs Grace's new venture -- Grace's Cafe. In the end, Dr. Mike saves the day by curing the mine owner's son, who has fallen victim to the poisoned water, and convincing the owner to close the mine.

Dr. Mike tries to heal the soul of Doc Eli, a Civil War surgeon turned patent medicine show huckster, who's come to like the taste of his own medicine, an all-curing elixir used by the fabled Kickapoo Indians. She doesn't trust the sales pitch of this exploitave medicine show man, especially when she's facing a real medical crisis involving Myra. She must help Doc Eli face his past demons, before he can help her remove an ovarian cyst from Myra, in a technique he pioneered. Meanwhile Sully's on a similar mission in trying to convince Franklin, a disillusioned Cheyenne, survivor of a massacre, to join his own people in their continuing fight for survival. Myra and Horace get engaged.

Dr. Mike takes in Red McCall, a down-and-out cowboy, and his ailing half-breed infant child. McCall reaches the end of his rope trying to care for his baby, so after robbing Loren's store, he leaves the baby in Michaela's care, sensing she could find a suitable home for his child. Dr. Mike's attempts to find a home for the baby prove futile. When she travels to a remote cabin to check on the health of it's owner, she finds him badly mangled from a bear attack. Her horse is frightened off by the bear, and she's marooned in the cabin until Sully shows up looking for her. They narrowly escape being the rabid bear's next victims. After returning to town, Dr. Mike decides she'd rather raise the child herself than turn him over to an orphanage. However, Sully locates Red and convinces him to keep the child.

Sully ends up badly beaten and partially paralyzed following a run in with buffalo hunters who were hired by the railroad to clear the buffalo and Indians out of the planned train path. As Dr. Mike, Cloud Dancing and the kids fight to help Sully regain the use of his legs, a con man who's passed himself off as an advance man for the railroad is in the process of swindling the townsfolk out of the deed to their property. Sully recovers and Dr. Mike unmasks the con man's plan thereby saving the townsfolk's property.