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.