Michaela "Mike" Quinn, of Boston, followed in her father's footsteps by becoming a doctor. Dr. Mike worked side by side her father. But his sudden death caused her the loss of, not only her best friend, but the loss of their medical practice. The lack of job opportunities for women doctors lead Michaela to answer an ad for a doctor in Colorado territory. Michaela left her fancy home in the city of Boston for the western town, Colorado Springs. When she arrives in town she is met with mockery, for they expected a man doctor. She is befriended by Charlotte Cooper (Diane Ladd) and becomes good friends with her. Charlotte and Dr. Quinn become close friends and when Charlotte is bitten by a rattle snake, she leaves her three children Matthew (Chad Allen), Colleen (Erika Flores, later Jessica Bowman) and Brian (Shawn Toovey) for Dr. Mike to look after. As the town continues to mock Michaela for expecting to be the town doctor, she meets Sully, a white man ""turned"" Native American who lets he

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.

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.

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

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.