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.

Snowbird gives Dr. Mike a horse she wants to enter in the Territory Stakes horse race, but she must disguise herself as a man to qualify. Sully teaches her what to do to fool the race officials and helps her with strategies for the race.

Loren's sister-in-law Dorothy comes to town to flee her abusive husband. He ends up dead, and she is tried for his murder.

Mike is forced to rethink her relationship with Sully after a visit from his ex wife's ghost.

While hunting, Jake accidentally kills the Cheyenne brave Little Eagle and Sully tries to keep the peace between the Cheyenne and the town.

Dr. Mike and the reverend are skeptical when a so-called religious healer comes to town.

Dr. Quinn's mother in Boston is ill. Dr. Quinn takes the children to Boston.

Dr. Quinn has met a very nice doctor in Boston and is conflicted about staying.

There is a drought and no food for the town's Thanksgiving dinner. The townspeople fight over water.

Dorothy thinks she's pregnant, but Dr. Mike's exam reveals there are other problems going on. The upcoming Sweetheart Dance causes trouble between Sully and Dr. Mike. Colleen and Becky squabble over a boy, while Dr. Mike suspects something fishy going on between Sully and Dorothy.

Dr. Quinn is called away to a Flu epidemic in another town. Leaving Sully in charge of the children. But when there is an explosion at the railway, the military puts a bounty out for Sully. Sully is shot, leaving Colleen to treat him.

Dr. Mike has an "A Christmas Carol" style dream, where she wonders what her life would have been like if she had not become a doctor.

When the silver miners strike, Matthew is eager to take a scab job mining for the quick cash. But, with disastrous results.

The army brings supplies to the Cheyenne as an offering for their land. Dr. Quinn advises them to take the supplies in order to ease their suffering through the harsh winters. However, the supplies harbor a hidden surprise for the Cheyenne.

When a former circus performer and her daughter bring their circus to Colorado Springs, most of the town is recruited as performers.

A woman who has been living with Native Americans for over ten years is found and brought to Colorado Springs. Tensions rise between Sully and Mike when the girl becomes unusually attached to Sully.

When Rev. Johnson sponsors an orphan train in Colorado Springs, he finds placing the children in suitable homes may be harder then he anticipated.

A troop of buffalo soldiers comes to town and with them the idea that the government was using them instead of white soldiers, because it was felt they were more expendable.

Matthew gets hooked on gambling. Rev. Johnson's past catches up to him.

Dorothy's son returns from war with a problem that many vets came home with.

The town hires a new school teacher.

Doctor Michaela is abducted by Native Americans.

With the help of Cloud Dancing and his son, Sully is determined to rescue Dr. Mike.

The town decides they need a town mayor. Jake Slicker and Dr. Mike are nominated to run against each other.

After Myra quits working for Hank, he drinks himself into a coma and Myra is the only one willing to stay by his side.

A stranger with close ties to Dr. Quinn comes to town with an agenda of his own.

Dr. Mike and the citizens of Colorado Springs look forward to the advantages a train could bring to their small town, but Sully and the Cheyenne fear progress could lead to their demise. While Loren and Jake are creating a false campaign of the town's highlights to lure the railroad developers to the area, Mike and Sully disagree about whether or not they should build their future and their new home in a town undergoing such change. While the engaged couple searches for a compromise, Colleen befriends a Chinese railroad laborer, named Peter, who has encountered hostile discrimination during his stay.

When Loren sets out to prove he's not too old, and Brian wants to prove he's old enough, the two embark on individual journeys that intersect. Loren shocks everyone when he announces that he's going to travel to Bolivia, to prove to himself and to everyone else that he's not too old for the treacherous adventure. While he's away, Brian takes off on his own little adventure -- to camp out alone at night and brave the elements. But an unexpected travel companion -- a grizzly bear -- unites the two "men" in a shared adventure neither anticipated.

Loren's sister, Miss Olive, has died and bequeathed her cattle to Matthew who, along with Dr. Mike, Sully, Colleen, Brian, Loren, Robert E, and Grace, attempts to bring the cattle back to a ranch near Colorado Springs.

The Cattle Drive continues with various difficulties to overcome including conflicts between Matthew and Sully, cattle rustlers, hungry Indians, and a prairie fire. Dr. Mike delivers a calf, and Sully helps her clean up afterwards.

Elizabeth sends crates of books from Michaela's deceased father's collection, prompting her to open a public library. Many become alarmed at the content of some of the books and want to prevent people from reading them.

Brian rescues a man from a trap who has horrific burns to his face from a train crash. Michaela decides to perform reconstructive surgery to repair his face.

Cloud Dancing and the rest of the Cheyenne are told to move to a reservation where they would be dependent on handouts. Dr. Mike, Sully, and the children head to Washington to lodge a complaint and get the order changed.

Arriving in Washington, Dr. Mike and Sully find it difficult to find anyone to listen to their concerns. Sully is arrested for army desertion while a plot against the president is overheard. Michaela must break Sully out of jail to expose the conspiracy.

When money becomes short for Sully, he tries everything to make ends meet rather than accept help from Dr. Mike.

Dr. Mike and Sully are traveling through obnoxious Native American territory when their stagecoach is robbed and they are abandoned. With them are a just married Kid Cole and Sister Ruth as they try and reach home for Thanksgiving. Evading hostile tribesmen is only the beginning.

Dr. Mike discovers a lump in Dorothy's breast and tries to convince her to have surgery. Hank tries Ladies Night at the saloon, and Jake and Loren have a plan to get free drinks. Colleen deals with hurtful boyish pranks from classmates.

Dr. Mike has a hard time accepting Dorothy's decision not to have the surgery that will save her life. Jake tries to escape the two men who kidnapped him.

The town's Christmas spirit is in question when a family who are Jewish immigrants moves to town.