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.

After ambushing Black Kettle's camp, General Custer enters the town carrying wounded soldiers and Indian prisoners, including Cloud Dancing, whom Custer threatens to kill if Dr. Mike does not treat his men before the injured braves. Later, Dr. Mike treats Cloud Dancing's broken arm while he remains shackled in the livery after Custer's interrogation. When Custer jokingly hauls Cloud Dancing before a firing squad that fires blanks, Dr. Mike and Sully engineer Cloud Dancing's escape. Meanwhile, Olive opens a Hurdy Gurdy, recruiting girls from the immigrant camp and a reluctant Loren, Horace and Jake for the band. Matthew buys all of Ingrid's dance tickets then shyly confesses that he doesn't know how to dance. Robert E. and Grace exchange looks. Robert E. is still burned from The Visitor (#3).

After a patient of Dr. Mike's dies of blood poisoning, she accuses Jake, the barber, of infecting the man with his dirty razor. Her accusation throws Jake into an alcoholic binge. Dr. Mike tries in vain to pull him out of it, but finally realizes he must be the one to want to stop drinking. She gives him something to live for by pointing out his many friends in town, including her. Meanwhile, Mike's children try to help her deal with her loneliness on her 35th birthday by conspiring to find her a proper suitor before her surprise party

Matthew's sudden announcement that he wants to marry Ingrid causes upheaval in his relationship with Dr. Mike, who feels he's too young. In an effort to prove he's man enough to make his own decisions, he convinces Sully and Cloud Dancing to allow him to partake in a four-day Cheyenne ritual. This is the final straw for Dr. Mike, and she confronts Sully before she storms off looking for Matthew. Meanwhile, Ingrid suffers asthma attacks, and her treatment is undermined by Dr. Mike's disapproval of their marriage plans. Dr. Mike comes upon Matthew going through the rite of passage and seeming at peace with himself, so she lets him finish uninterrupted. Later, Dr. Mike and Matthew resolve their differences, with him deciding to delay the wedding and her giving Matthew her engagement ring for Ingrid.

Colleen develops a teenage crush on Sully after he pulls her out of the path of a runaway wagon. Imagining herself as a damsel in distress and Sully as her knight in shining armor, she purposely sets out to get lost in the woods hoping Sully will rescue her. A freak cold snap blows up and she almost freezes to death before Sully and Dr. Mike find her. Dr. Mike works hard to save Colleen's badly frostbitten hands, and Sully ultimately has a heart-to- heart talk with Colleen. Meanwhile, racial tensions in town reach a boiling point when Hank accuses Grace of food poisoning which is later proved false when Dr. Mike discovers Hank has been eating meat infected with trichinosis.

While Brian and Sully are out hiking, Brian climbs a tree and jumps out before Sully can stop him. Brian lands hard, hitting his head. Mike, angry with Sully for not watching Brian more carefully, is relieved to find no signs of injury. Later, the townsfolk argue over who will build the new schoolhouse, Matthew wants Robert E included, but, in the end Jake and Loren are tapped for the job. Brian begins to exhibit symptoms of compression, which escalate to blindness and later, coma. A specialist can't be found and Mike must perform a dangerous brain operation while Jake and Grace assist. Meanwhile, the town, including Robert E, pulls together to build the schoolhouse. Brian awakens and wanders out to the new school where Mike and the family find him, overjoyed that he can see again.

When Mike and Sully stop to check on old Mrs. Johnson, they discover her dead and a young boy, Zack, hidden in the closet. Mike takes the child in and confronts the townsfolk, who reluctantly admit to knowing the boy's mother was one of Hank's whores. When she died they sent Zack to Mrs. Johnson because he was ""simple."" Mike is frustrated in her attempts to find a medical diagnosis and cure for Zack's condition. Mike's further detective work reveals that Hank is Zack's father, and she helps Hank own up to his responsibility. Meanwhile, Brian seems to be the only one to get the boy to exhibit his artistic abilities, and he is mistakenly given credit for a drawing that Zack has done. Later, when Zack's artistic talent is discovered, Hank agrees to send him to an art school in Denver. The show has a cute opening scene of Mike and Sully with him criticizing her driving.

David Watkins, a civil war photographer arrives in Colorado Springs. Dr. Mike diagnoses David's diabetes and is frustrated that he refuses treatment and will ultimately go blind. David suggests taking a portrait of the town and an argument ensues over who will be in it. When the camera equipment is destroyed, the whole town must pull together to create a camera and take the photo before David's eyesight fails. At the same time, Mrs. Bing, Horace's mother, is brought to town, seriously ill. Mrs. Bing disapproves of Myra until she learns how much they love each other, and on her deathbed bestows her blessing on their marriage.