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

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.

Sully ends up badly beaten and partially paralyzed following a run in with buffalo hunters who were hired by the railroad to clear the buffalo and Indians out of the planned train path. As Dr. Mike, Cloud Dancing and the kids fight to help Sully regain the use of his legs, a con man who's passed himself off as an advance man for the railroad is in the process of swindling the townsfolk out of the deed to their property. Sully recovers and Dr. Mike unmasks the con man's plan thereby saving the townsfolk's property.

Jake, Loren and Horace are out hunting when Jake, mistaking an Indian for a deer, accidentally shoots and kills him. During the melee, Horace is wounded by an arrow, which Mike treats. Loren and Jake, frightened and guilty, try to cover up Jake's blunder by declaring that the Indians attacked. They persuade Horace to participate in this lie. Sully and Mike are caught in the subsequent hostilities between the Indians and townsfolk. The incident threatens to provoke an all-out Indian war, as well as a rift between Sully and Mike and between Sully and Cloud Dancing, until Mike elicits a confession from Horace and Sully intervenes to bring peace. Eventually, the Indian tribal council declares that Jake must make financial reparations to the dead Indian's family, including his horse, watch and ring.

Mike and Sully work to treat a typhus epidemic at Black Kettle's camp, which begins after Mike and Sully unwittingly convince Black Kettle to accept government blankets infected with the virus. Mike is heartbroken and guilt-ridden as she battles the tribe's typhus epidemic. When Matthew comes down with typhus, the town panics and locks the children in the clinic alone with Horace. Colleen treats Matthew and Horace contrives to send the kids out to the reservation to be with Mike. Meanwhile, the town prepares for the Fourth of July, ironically missing the point entirely that the first Americans, the Indians, are being systematically wiped out and further, that the newest Americans, the Immigrants, have just had their camp destroyed by the typhus-fearing townsfolk

A troop of black cavalry soldiers ride into town intending to cover themselves in glory by eradicating hostile Dog Soldiers who've been attacking the railroad. Mike commits an act of civil disobedience by tipping off the Indians, which results in carnage on both sides and the defeat of the Buffalo soldiers. She's accused of treason, and jailed, but the arrogant black cavalry leader,

Sergeant Zachary Carver, manages to exonerate her when he's made to realize, through the combined efforts of Sully and Mike, that his beloved troops are nothing more than pawns in the U.S. Army's policy of genocide against the Indians. Returning the favor, Mike manages to medically fake the Sargeant's death, and he escapes court martial.

Meanwhile, Colleen cheats on a test and by doing so manages to win a school trip to Washington. Mike must then explain the concept of ""good lying;"" that is, civil disobedience for a principle, and ""bad lying,"" that is, Colleen's self-serving actions regarding the test. In t

Sully takes a job as an Indian Agent, only to discover corruption's rife within the system. Meanwhile, liquor arrives on the reservation, and Snow Bird miscarries due to malnutrition.

Mike and Sully arrive too late to avert Custer's slaughter of the Indians at the Washita River; Brian befriends an Indian boy destined to die at Washita; Robert E & Grace attempt to adopt an Indian baby whose mother was killed at Washita. No Harm Comes To Him: Sean Price-McConnell.

Sully and the kids must help Mike deal with the emotional aftermath of the Washita massacre; Robert E and Grace must return to Cloud Dancing the Indian baby Mike and Sully brought back from Washita

Mike and Sully go to the Reverend for a dose of preventative pre-marital counseling, and recall the path of their romance.