Michaela Quinn, a female doctor in post-Civil War Boston, Massachusetts, finds more than she bargained for when she answers an ad for a doctor in a small town in the Colorado territory.

Miss Olive arrives back in town and believes that she should be the one looking after Matthew, Colleen and Brian. She brings with her a sick cowboy who had contracted influenza but everyone is unaware of the exact nature of his illness. Michaela attempts to try her hand at cooking but is unsuccessful. After the cowboy dies and his child becomes ill with the same thing Dr. Mike discovers that it is influenza. People in the town were dying and Dr. Mike wanted to quarantine people who are sick in Charlotte's boarding house. Brian comes down with the influenza and Colleen begins to think that Dr. Mike only wants to treat people instead of being their guardian and starts to resent her. Dr. Mike is running out of medicine and Sully suggested Cheyenne brewed tea but she does not want to administer a drug she is not familiar with. Dr. Mike uses the last bit of medicine for Jake, Brian and Horace. Brian's fever finally breaks and Dr. Mike is relieved but she herself now has influenza. Sully had Matthew go for Cloud Dancing, Medicine Man. Will they get back in time?

Dr Mike's upper-class mother visits from Boston, disapproving of her daughter's choices, acquainting herself with her daughter's new family. Robert E suffers burns. Dr Mike is evicted from her makeshift clinic by the bank.

When a starving orphaned immigrant takes desperate measures to feed his siblings, the only thing standing between him and a noose is Kid Cole, the new sheriff.

Loren, the unforgiving father-in-law, threatens to take back Sully's homestead.

Michaela worries when Charlotte's husband, Ethan Cooper, comes back to the family he abandoned, convincing almost everyone of his newfound ways.

When the town's water supply is tainted with mercury by a wealthy mining baron, many people become sick and Dr. Mike threatens the miner to clean it up or have his land taken away.

When Doc Eli, a medicine-show man, arrives in town professing to have created the perfect bottled elixir, Mike sets out to call his bluff, especially when her children's health becomes jeopardized.

A wandering cowboy abandons his baby boy and leaves him in Dr. Mike's care.

The railroad hires men to kill off all the buffalo, which the Cheyenne need to survive, and Sully gets hurt when he tries to stop the men.

When Cheyenne medicine man Cloud Dancing is wounded by General Custer, who intends to hang him, Sully and Dr. Mike join forces to help him escape.

As Dr. Mike's birthday approaches, the kids decide to do something about her unmarried status

Matthew and Michaela are at odds over his future when he sets out to prove to others -- and to himself -- that he's a grown man ready to take on life -- and decides to marry Ingrid.

Colleen believes that she loves Sully and that he returns her feelings when he saves her from a runaway wagon. She and her friends had been reading romance stories in a weekly publication and in one of them the woman is captured but writes a letter to her love, and he saves her. She decides to write a letter to Sully and goes into the mountains in hopes that he will find her. Lewis finally gets the letter to Sully by giving it to Dr. Mike who reads it first and informs Sully of what was going on. Hank accuses Grace of trying to poison him with her cooking.

While out on a walk with Sully, Brian climbs a tree to show he could fly like the eagle in Sully's story but falls and hits his head. At first every thing seems fine and the town gets ready to build a school house. Brian is really excited about it and goes to help Loren but loses his sight. Loren rushes him to Dr. Mike. Although she is certain of what it is she does not know how to fix it. She wires for a doctor in Boston to advise as to nearest specialist. Dr. Mike refuses to leave his bed side and when they finally get word that the specialist is coming they find that he had slipped into a coma. Sully finally shows back up after being gone for two days and Michaela being so scared blames Sully. When they find that the stage coach will take longer to get here Dr. Mike realizes that there is no other way but to do the operation herself.

A woman dies and they find a hidden boy at her house. Dr. Mike takes the boy in while they try to determine who he is and if he has any family.

A famous civil war photographer realizes he may be taking his last picture after Dr. Mike discovers that he is going blind.