Michaela 'Mike' Quinn narrates her childhood about how she was born on 1833 in Boston, Massachusetts, as the last child to a family of five children, all of them girls. She explains how she wanted to attend Medical School, but none would accept women, and she finally received her M.D. from the Women's Medical College in Pennsylvania. She became a partner in her father's office and worked with him for 7 years, until his death. The practice ended, and Mike thought her career as a doctor was over. Mike reads an advertisement for a town doctor in the Colorado territory. After sending a telegram, she is offered the position in less than a week at the frontier. Packing her belongings, Mike bids goodbye to her mother and sets off to Colorado Springs.
As she reaches Colorado Springs, Mike steps out of her carriage, and asks a man where Rev. Johnson would be. He tells her to go to the church, and as Mike walks to the church, she nervously sees all the people staring at her. She meets Rev. Johnson and introduces herself as the new medical doctor. The Reverend is surprised as he was expecting a male doctor named 'Michael'. He asks her to come with him, and as they start walking, Mike sees a negotiation taking place between the Colonel and the Indian Chief for land, and she accidentally trips and falls on the muddy ground. Rev. Johnson helps her up and takes her to a man named Horace, and asks him if he changed Mike's name in the telegram. Horace mentions that he removed the 'A' from Michaela thinking that it was a middle initial that was not required. Rev. Johnson is embarrassed and tells Mike that he would arrange for her trip back to Boston. Mike refuses to go back and firmly tells him that Colorado Springs needs a doctor and she happens to be one. Rev. Johnson thinks it is a bad idea since no single women in Colorado Springs are considered respectable, and no one would approve the idea of a woman doctor.
He takes her to Charlotte Cooper, a single mother of three children, to board a room, hoping that Charlotte would be as disappointed with the situation as he is. However, Charlotte is pleased to meet Mike and introduces her three children, Matthew, Colleen and Brian, and invites Mike inside. She accommodates a room for Mike and asks Rev. Johnson and Matthew to bring the luggage to her room.
In the evening, as everyone sits down for dinner, Mike tries to start a conversation with Colonel Chivington on how the treaty is progressing with the Indians. Mike feels that since the Indians were on the land first, they have a right to it, but the Colonel gets frustrated and mentions that they are in the way of progress. Charlotte changes the subject by asking Mike if she is engaged, and Mike mentions that she was once. Charlotte starts talking about the men in Colorado Springs but Mike is not interested. She asks Charlotte where the newspaper office to post an advertisement, and Charlotte tells her that it's in Denver, but she can go to Bray's store to post an ad.
The next day, a man named Jake Slicker tells Rev. Johnson that Colorado Springs should not have a woman doctor and that Mike should be sent back. Charlotte tells Mike that Jake considers himself a doctor just because he has pulled a few teeth and lanced a few boils. Charlotte tells her that the only doctoring allowed to women is 'midwifin'. As they enter the store, Loren, the man Mike had first met on her arrival, finds out that Mike is the woman doctor and tells them that there's no room to put up her notice. Just then an Indian Chief accompanied by another man enters the store. Loren points to the sign saying 'No Dogs and Indians', and Mike removes the sign, telling Loren that the notice itself is outdated for the board. Chivington, who is also in the store, angrily takes the sign from Mike and hangs it up again, but the man accompanying the Indian Chief throws his tomahawk on the sign, breaking it in two. Chivington scowls at them and leaves the store. As the man goes to get his tomahawk, he looks at Mike and the sign that she posted up for 'permanent lodgings'. Charlotte drags Mike out the store, and later tells her that being a single, unmarried, and woman doctor wouldn't get her the respect that she deserved, since some people in Colorado Springs don't even treat Indians as humans.
Charlotte and Mike head to the Livery to purchase a new horse for Mike, in order to make her rounds to her patients. Mike doesn't seem to know much about horses, and tries to get on one to ride it, but cannot seem to get up. As she tries to get on the horse, someone pushes her to the seat. After adjusting herself, she looks down to see the same man who was accompanying the Chief. He hands her the notice that she put up in the store, telling her that he is answering to it. He takes her to an abandoned cabin outside town. Mike goes to the cabin and asks him how much, and the man replies a dollar a month. Mike agrees, and from her purse, takes out the plaque with her name on it, and displays it in front of the cabin, asking the man what he thinks of it. The man tells her that it's not much of a shingle, and walks away.
The next day, as Mike travels with Charlotte and her children from the town with her supplies, Charlotte tells her about Sully, the man that helped Mike find the cabin. She tells Mike about how Sully was in love with Loren's daughter Abigail, that the cabin actually belonged to them and that Abigail died while giving birth to Sully's child. Loren blames his daughter's death on Sully. They reach the cabin, and Mike starts cleaning by trying to dust the floors with a broom. Charlotte realizes that Mike has no experience in using a broom, just as with horses, and teaches her how to sweep the floors. Brian takes out a mallet from Mike's bag and asks her what it is. Mike explains how hitting the mallet in the knee tells her something about his brain. Matthew finds it silly but Colleen seems interested. After they help her around the house, Colleen teaches Mike how to get eggs from the chickens' nests. Afterwards, Mike thanks Charlotte and the children for helping her out, and Charlotte wishes her luck, emphasizing that she would need it. The night, Mike finds that Sully left the cabin just as it were when Abigail was alive. She sees Sully and Abigail's wedding picture, the baby clothes and toys, and feels like an intruder in someone else's cabin.
The next day, Mike goes to town for church and meets Charlotte and the children. She also sees Chief Black Kettle pointing at her and telling Sully something. She tries to introduce herself to the other town members, but they all turn their backs on her. Suddenly, Hank, the bartender, yells out that a man has been shot, and half the town men run to find out what's wrong. Mike runs after them and goes to the wounded man to treat him, but they push her away. The men carry the man and take him inside. As Mike follows them, she notices a woman breathing heavily. She removes her stethoscope to examine her, but Loren comes and prevents her from doing so. The woman is Maude, Loren's wife. She insists that she is all right, but before Mike can protest, Loren drags his wife away.
Mike gets upset and goes to Sully. Sully is in a small cemetery, kneeling over the grave of his wife and child. As he gets up, Mike tells him that some of his things are still in the cabin and asks him what Chief Black Kettle was telling him earlier. Sully tells her the he wanted to know who she was, and once he found out, the Chief told him that only men made medicine, and she was a crazy white woman.
Other than Charlotte, no one takes Mike seriously as a doctor. One day, Matthew comes to her cabin- Charlotte needs her help. Charlotte is helping a woman named Emily give birth. Charlotte tells Mike that something's wrong, and Mike examines Emily. She realizes that she needs to cut Emily open to get the child out, and tells Charlotte to make Emily inhale a cloth of chloroform. Charlotte reluctantly follows her orders, and Mike successfully removes the baby. She hands it over to Charlotte, but the baby is not crying. Mike tells Charlotte to hold the baby upside down and slap it, and the baby starts crying. Emily wakes up and Mike lets her hold her child.
A few days later, Mike realizes that even though Emily healed well and the baby was healthy, she still wasn't getting any patients. Taking drastic measures, she goes to Jake Slicker, and tells him that she has a toothache and wants his opinion on it. Jake brings her inside, with the townsfolk watching. Mike sits down and Jake looks at her teeth. As he is studying her teeth, Mike sees an infection on Jake's hand. Jake uses the pliers and very painfully removes the tooth. Mike thanks him for his services in front of everyone, and hands him the money and a bottle of medicine for his infection. She leaves the store and goes to see Charlotte. She tells Charlotte about the incident with Jake, and Charlotte applauds her for her guts. Mike asks Charlotte how her husband died, and Charlotte mentions that he didn't, and that the townspeople only call her widow to be nice to her. She tells Mike that her husband left with her money. Charlotte asks Mike about her fiancée, and Mike tells her how he suddenly decided to go to fight for the war, and died there. She tells Charlotte that her fiancée was also a doctor. Mike couldn't meet men by going to parties like her sisters- they thought she was too smart for them. So she focused on her work, until she met him. They share the pain of losing a loved one.
Mike comes out and sees Sully walking by. She goes to him and asks him how the negotiations went between the Colonel and the Chief. Sully tells her that Chivington threatened to go to war with the Indians unless they surrendered their land. Mike is upset by this, and Sully tells her that Chivington only wants to steal the land so that he can become First Governor.
One day, Jake Slicker comes to her cabin and thanks her for the ointment that she gave him for the infection. He tells her to go see Robert E., the blacksmith, about his lumbago, mentioning that he asked Robert E. to let her examine him, since he was getting tired of his whining. Later, she goes to see Robert E., and first thanking him for the horse. Getting into the subject of his lumbago, she takes his hand and asks if she can examine him. He pulls his hand away and tells her that he doesn't want to be examined by a woman doctor. She angrily tells him that of all the people, she would have expected him to know how it was like to be treated unfairly. Robert E. calms down and pulls out his hand. Mike diagnoses arthritis, and gives him a powder to alleviate the pain. Robert E. says that the medicine would have to do till the new doctor arrived. Mike is shocked by this, and Robert E. explains that Rev. Johnson put out another advertisement for a new doctor.
Mike goes to see Rev. Johnson and asks him why he is looking for a new doctor. They get into an argument about why Mike shouldn't be considered working as a doctor since she is a woman, when Brian runs up to them and yells out that Charlotte needs help. Rev. Johnson and Mike go to see Charlotte, who is lying on her bed, deathly ill after being bitten by a rattlesnake. Charlotte asks Mike to take care of her children once she passes away, and Mike agrees to her final wishes. Charlotte dies, and her children start crying.
Later, at Charlotte's funeral, the children, especially Matthew, are hostile towards Mike. Mike narrates that Charlotte had many unpaid bills, and because her boarding house closed, the children came to live with her. When the children arrive at Mike's cabin, Matthew is very rude to Mike, telling her that what they brought belongs to them and not her, and insists on living in the barn. Mike asks him if they can learn from one another, but Matthew just stares at her. Brian gets upset and starts running away from the cabin, but Matthew runs up to him and stops him. Mike tries to soothe Brian, and Brian holds her tight and starts crying.
A few days later, Mike goes to town with the children to shop and to send a letter to her mother, asking her for advice on child rearing. In Bray's store, Brian drops a jar of candy, which shatters on the ground. Mike agrees to pay for the damages, and Loren asks who is going to clean the mess. Mike tells Brian to do it, and Brian replies that he hates her. Upset, Mike later notices Maude having breathing problems again. When Loren goes to the back room, Mike secretly hands Maude some medicine for her pain. She tells the children to wait in the store, and goes to the post office to send her letter. She notices Horace having trouble with his hearing. She examines Horace's ear and removes a lump of wax from it. Horace is happy to hear clearly again, and offers to send Mike's telegram with no cost.
When Mike comes out of the post office, she goes past the saloon, where she hears someone cry out to her for help through the window. She goes inside the saloon and sees Myra, the saloon girl. She goes to see her, when Hank tells her that no women are allowed. Mike tells him that she's not a woman; she's a doctor and goes inside Myra's room. She diagnoses Myra with 'female problems', and tells her not to perform any 'activities' for a month. Myra is nervous at the thought of Hank not liking the idea, and Mike tells her that she will talk to Hank. Myra gives her a necklace as a thank you Mike goes to Hank and tells him that Myra cannot do any work. Hank doesn't take her seriously, and one man gets up from his table and prevents Mike from leaving the saloon. Sully comes behind him and starts fighting with him and the other men. Sully and Mike escape from the saloon, and Mike runs up to the wagon, and tells the children to hurry. Before taking off, she thanks Sully for helping her.
On their way back to the cabin, Mike realizes that Brian is still angry with her for the candy jar incident at the store. The next morning, when she checks up on the children, she sees Brian's bed empty. She tells Matthew to look after Colleen and takes the horse to search for Brian. She rides on for a long time, searching for Brian, even getting ambushed by the Cheyenne.
The Cheyenne bring Mike back to their territory and push her inside the Chief's tent, where Mike sees Sully. Mike asks Sully to make the Indians let her go. Sully tells her that the Indians brought her here for safe keeping, since she looked lost. Mike admits that she was lost and tells Sully about Brian. Sully talks to the Chief in their native tongue and tells Mike that the Indians will look for Brian since there is still some light outside, and bring him to her if they find him. Mike thanks Chief Black Kettle for his generosity. They go outside the tent, and sit by the fire. Sully gives Mike some corn to eat. Mike doesn't feel hungry and wants to leave, but Sully tells her that if she wants to search for Brian in the morning then she would have to eat. As Mike eats the corn, she remembers her past, and gets homesick. Mike feels like she let Charlotte down, and Sully reassures her by saying that she didn't and tells her that life just has a way of taking its own course. He takes a blanket and wraps it around Mike to keep her warm and later they fall asleep.
The next day, Rev. Johnson, Jake, Loren, and Matthew starts looking for Brian on their own. On their way, they also see the Cheyenne and Loren wonders if they are up to anything, but Matthew and Rev. Johnson calm him down. Meanwhile, Mike and Sully are searching. Sully's wolf finds a piece of Brian's clothing, and starts to track him. They find Brian lying midway on a steep cliff, and Sully carefully climbs down and rescues Brian. Brian hugs Mike, and Mike examines him for wounds. She finds he has a broken leg and splints it painfully. Later, as they walk down the hill, Sully, Mike and Brian meet the Cheyenne. They also see the troop of soldiers, headed by Colonel Chivington, across the land. Chivington orders them to charge, and the troop starts coming forward to fight the Indians. Mike runs in front of Chivington and his army of men, yelling them to stop. They come to a halt, and Mike explains that the Indians were searching Brian. She apologizes to Chivington for the inconvenience, and Chivington backs away with annoyance and leaves. Matthew meets Brian and thanks Mike for her help.
A few days later, after Brian's wounds heal, Mike and the children shop in town again. Mike buys Colleen a new dress, and Loren says she spoils the children. She also sees Brian looking at a wolf sculpture similar to Sully's wolf. Loren mentions that Sully made that wolf, and Maude explains that the sculpture belonged to Abigail. Mike decides to buy the wolf sculpture from them, when Maude suddenly collapses on the ground, clutching her chest. Mike asks her where the powder she gave her is, but she used it all. Mike runs to the post office to see if her parcel from Chicago with more medicine arrived, but she can't find it. She runs back to the store and tries to help Maude, but it is too late. Maude dies, and Mike is crushed that she lost a patient, 'due to want of a simple drug'.
That night, Mike reads the letter from her mother to the children. She starts crying when she reads of her mother's disappointment in her, urging her to come home. Late that night, Sully knocks on the door. He brings in a bleeding Chief Black Kettle. Chivington and his men ambushed the Cheyenne territory, massacring most of the Indians; and the Chief was shot. Mike gets her supplies and immediately starts operating on Chief Black Kettle. Mike is able to remove the bullet from the Chief. Sully wants to hide the Chief since Chivington and is looking for him, but Mike says the Chief can't be moved until the swelling comes down. While they wait, Mike asks Sully how he got involved with the Indians. Sully tells her that many people think that the wolf is scary, but the wolf is a friend, just like the Indians. When the first white man came, there were thousands of wolves, but now there are just a few hundred, also like the Indians.
The next morning, Sully takes the Chief to the barn to hide him from the search troops. Mike cleans up the house, getting rid of all the bloodstained clothing. When the search troops arrive, they search the house; one of the soldiers decides to check the barn. Sully sees the troops coming, and helps the Indians carry the Chief outside through the back door of the barn. The troops leave, suspecting nothing. Later, Mike and the children bid farewell to Chief Black Kettle and his tribe. The Chief gives Mike her Cheyenne title of 'Medicine Woman'. Brian asks why Sully won't ride with them, and Sully admits he's afraid of horses. He bids them farewell and takes off.
The months pass and soon Christmas Eve arrives. Colleen is looking forward to the Christmas Dance, but they are snowed in atthe cabin. Matthew is in a fowl mood and tries to scare Brian with the story of the 'snow monster'. Colleen starts crying at the thought of missing the dance. Mike starts singing Christmas Carols and soon the children happily join her. Later, as they say grace and start to eat, Sully knocks on the door. He brings gifts for everyone, including a large name plaque for Mike. Mike looks at everyone around her and narrates how lucky she is to have found a family, and a place filled with love.