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?
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 Lorne but loses his sight. Lorne 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 2 days and Michaela being so scared blames Sully. When they find that the stage will take longer to get here Dr. Mike realizes that there is not other way but to do the operation herself.
Loren plans a trip to Bolivia to prove he is not getting old; Brian seeks to prove his courage by camping out alone. The two become inadvertent allies as they battle the advances of a hungry bear. Also, Jake and Hank's practical jokes get out of hand, culminating in injuries to them both, until they agree to make up.
Ah abrasive Dr. John Porter arrives in town after hearing of the discovery of dinosaur bones. After learning they were found in a sacred Indian burial ground, he proceeds to spoil grave sites under the protection of the US Army. Cloud Dancing and the Cheyenne retaliate by taking the remains of the white settlers.
The town of Colorado Springs is preparing for the an event of a lifetime, the marriage of Sully and Dr Mike. Unexpected guests include Elizabeth Quinn and Rebecca and Marjorie. Dr Mike's mother and 2 sisters. They have brought with them enough Boston finery to pull off a splendid society wedding. Meanwhile Gen Custer has put out a bounty on Cloud Dancing which could interfere with the wedding.
Bolstered by the long-awaited arrival of the railroad, the citizens of Colorado Springs busily prepare for the biggest social event in the town's history, the wedding of Dr. Mike and Sully. The first train carries some surprise visitors, Dr. Mike's mother, Elizabeth, and sisters Marjorie and Rebecca, who have unexpectedly traveled all the way from Boston for the occasion. However, their elaborate wedding plans threaten to ride roughshod over the townsfolk's more homespun arrangements. Sully, meanwhile, is crestfallen to learn that Gen. Custer has placed a bounty on the head of his close friend Cloud Dancing, who he had planned to have as his Best Man.
Finally ready to work again after giving birth to her baby, Dr. Mike must lead a rescue party when Sully and Cloud Dancing are among the passengers on a train that has been overtaken by robbers and wrecked. Sully had negotiated Cloud Dancing's release from Army detention, and the two were taking the train to Colorado Springs when a gang of thieves derailed the train in an effort to rob it. Meanwhile, Dr. Mike must again face the prejudice against women doctors when she finds that the townspeople have become used to being treated by young Dr. Andrew Cook who filled in for her while she was on maternity leave. For his part, Andrew has become reluctant to return the practice to Dr. Mike and go back to Boston, as originally agreed.
Dr. Mike desperately attempts to find out why patients are dying mysteriously after having been treated in her clinic. As Dr. Mike searches for the answer to why a deadly and mysterious infection haunts her clinic, the townspeople begin to fear coming in for treatment. Unable to find out what is causing the deaths, Dr. Mike then makes a fateful decision that could mean destroying everything she has worked for through the years. Meanwhile, the attraction between Colleen and Andrew grows while she is home from college for a visit.
When Colleen, who is working on a college paper, asks Dr. Mike to recall her most memorable case, Dr. Mike looks back on the five turbulent years she's lived and loved in Colorado Springs. As they sit with Andrew, who is mysteriously ill at the clinic, Dr. Mike reminisces about her tumultuous career -- its successes and its failures -- and realizes how many divergent cases she as seen and treated. When Andrew's condition takes a turn for the worse, Dr. Mike warns Colleen about the fine line between emotional involvement and professional detachment, an issue with which she has long struggled in the frontier town that's now her home.
Sully and Brian forge a true father-son bond when Brian's free-wheeling, irresponsible adolescent behavior puts him in mortal danger, and Sully disciplines him. As Brian's stepfather, Sully has let Michaela set the rules for Brian up to now. But when Brian's misbehavior with his friend Anthony puts them, and the town, in danger, Michaela and Sully realize that Brian needs -- and wants - Sully to act as Brian's real father and give the boy the boundaries he needs, which enhances and strengthens their bond.
Marjorie, Dr. Mike's sister returns to town as a member of the Women's Temperance League to try to outlaw alcohol. Jake starts believing that there may be something going on between Hank & Ms. Teresa. Meanwhile Grace has turned to drinking to help comfort the recent death of her adoptive son Anthony.
Dr. Mike tries to prevent Loren from leaving Colorado Springs when she learns he secretly plans to sell his store and move away out of grief over the death of Marjorie. Meanwhile, the town prepares for its annual "Sweethearts Dance," but melancholy seems to reign. Jake broods over how to ask Teresa to marry him, and Grace's continued drinking threatens her marriage to Robert E.
Dr. Mike's elation at Colleen's acceptance to medical school quickly turns to disappointment when Colleen chooses to marry Andrew before starting school. A bitter family argument erupts when Dr. Mike tells Colleen that she is less than overjoyed at her announcement and feels that the couple is rushing into marriage and should wait until Colleen completes medical school. Meanwhile, Jake's sale of his half of the Golden Nugget to Preston angers Hank; Robert E and Grace have wonderful news to share; the stock market crash hits Preston and the townsfolk hard, and Dorothy and Cloud Dancing reach a new level in their relationship.
As Colorado Springs' Commissioner, Sully opposes a deal to mine for copper to make electricity. In order to sway Sully's decision, Mr. Garrick threatens Sully. Sully and Michaela's daughter, Katie, is kidnapped while the town celebrates Michaela's birthday. The search for Katie takes Sully, Michaela, and their friends on an adventure through Mexico that is filled with danger at every turn.
This final Dr Quinn episode is set 3 years after the end of the series. Dr. Mike and the family travel back to Boston to attend Colleen's graduation from Harvard Medical School. Colleen experiences the same prejudices as Dr. Mike, while Elizabeth Quinn is found to be seriously ill. Sully gets caught up in a land conspiracy while Brian finds a job with the Boston Globe. The series comes to a conclusion with a series of resolutions and a touching finale.