One morning, while collecting plant samples at the stone circle, Claire falls through the cleft in the main stone and is transported back in time to 1743. Upon moving away from the stone circle, Claire immediately runs into a battle between a group of local Highlanders, and British officers led by Jonathan Wolverton Randall. Randall, who demonstrates an amazing physical similarity to his six-times great-grandson Frank, assaults Claire, but she is rescued by Murtagh Fitzgibbons Fraser , one of the Highlanders, who are cattle-raiding in the area.
Murtagh takes Claire to a cottage wherein she meets Dougal MacKenzie, Rupert MacKenzie, and the other clansmen, who at first (since she is dressed only in a modern cotton dress) take her for a prostitute. Also in the cottage is an injured young man named Jamie, apparently a kinsman of Dougal's. Claire, starting to suspect that she may no longer be in modern Scotland, announces that she is a nurse and sets Jamie's dislocated shoulder and binds his bayonet wound. This demonstration is enough for Dougal to decide to bring her along, although he and the other men are startled at her tendency to use strong language. Claire rides with Jamie, and the two strike up a tentative friendship.
The group takes Claire to Castle Leoch, the seat of Clan MacKenzie, where she is presented to Dougal's brother Colum. It is in Colum's library that Claire finally realizes she is in 1743. Her story of a widowed English lady beset by highwaymen is more or less accepted by Colum, and she is shown to the chambers of the last castle healer, where she promptly sets up a modest nursing practice. Claire continues her friendship with Jamie, who tells her many interesting stories of his past, but never his full name or his family's history. He teasingly begins to call her "Sassenach," the Gaelic translation of "outlander" or "Englishman"; the nickname later becomes a term of great affection. Claire also befriends the procurator fiscal's wife, Geillis Duncan, and meets a young girl named Laoghaire MacKenzie, who falls madly in love with Jamie.
Colum, unsure whether Claire is a French or an English spy, sends her with Dougal and a large group of clansmen (including Rupert, Jamie and the elderly lawyer Ned Gowan) to collect the clan's yearly rents, for her to speak with the commander of Fort William about reconnecting to her (fictional) distant French relatives. During the journey, Claire learns that Dougal is a secret Jacobite, collecting money to raise an army for the exiled Stuarts.
The commander of Fort William is, of course, Captain Jonathan Randall, who thinks Claire is a spy for the MacKenzies and threatens to have her hanged. Unable to think of any other way to protect her from Randall, Dougal retrieves Claire from the English and forces her into marrying Jamie. She learns his full name just before the wedding ceremony, which takes place in the same small church where she and Frank were married almost two hundred years in the future. Claire, stunned by the quick turn of events, finds solace in married intimacy with Jamie, who reveals that he has been in love with her for some time, and was more than happy to marry her.
Jamie reveals much more of his past, including his childhood in Lallybroch and the years before he was sent to France to join the army. He tells Claire the events of his life which involved Jack Randall, including arrest, the rape of his sister, floggings, and homosexual advances. Jamie and Claire grow closer and closer as the group travels around the countryside, and by the time they reach the location where modern-day Inverness would be located, Claire is very much in love with Jamie. Regretting that she will break his heart by running away, she tries to reach Craigh na Dun on her own and return to Frank. She is caught, however, by one of Jonathan Randall's staff, and is brought to the English fort he commands.
Jamie and the other men rescue Claire from the English, committing arson, murder, and assault in the process, and flee back towards Castle Leoch. Claire doesn't at first realize what serious danger she caused, and is furious when Jamie calmly announces he must beat her for disobedience. Afterwards, however, the other men treat her more kindly than before, and she and Jamie make up when he tells her stories of being whipped for disobedience as a boy, although she threatens to disembowel him if he does it again.
The group returns to the seat of Clan MacKenzie, where Claire encounters the now-jealous Laoghaire. Jamie finally buys Claire a wedding ring, a woven silver band engraved with thistles; she wears it on her right hand, opposite Frank's gold wedding ring. Claire becomes friends once again with Geillis Duncan. One day, they encounter a child abandoned on a hillside. Claire's natural compassion moves her to try to save the child, but Geilie stops her, saying the parents consider it a changeling. She is seen with Geillis and Jamie on the hillside; the child later dies. Geilie's husband mysteriously dies a few days later, and before Jamie leaves on a stag hunt, he warns Claire to stay away from the widow, since she is now rumored to be a witch.
Left alone in Leoch, one day Claire trustingly follows Laoghaire's instructions to visit an apparently ill Geilie. But upon arriving in Cranesmuir, Claire is seized along with the perfectly healthy Geilie and thrown in the thieves' hole to await trial for witchcraft. Geillis tells Claire that she killed her husband when he learned she was pregnant. She also reveals that the child is Dougal's, and that she (Geilie) is also a fervent Jacobite.
When the trial begins, Ned Gowan arrives to defend Claire; his efforts lead the judges to have the women thrown in the lake (to see if they float) rather than burning them outright, but Claire's sharp objections cause them to have her flogged. As she is being whipped, Jamie arrives and dramatically throws a set of jet rosary beads onto her neck, proving that she could not be a witch. Geillis helps to distract the crowd by proclaiming that she, but not Claire, is a witch: as Geilie strips off her gown to reveal her secret pregnancy (saving her from being executed), Claire sees a vaccination scar on the other woman's arm, proving that she, too, is a time-traveller from the twentieth century.
Claire confesses everything to Jamie after they flee Cranesmuir, telling him about her time-travel and why she is not technically a witch. Jamie accepts everything, and takes Claire to Craigh na Dun, urging her to return to the twentieth century. She is torn between going back to Frank, from whom she has been missing for almost six months, and staying with Jamie, whom she has come to passionately love. With a great deal of torment, she eventually chooses to stay with Jamie, and he takes her to Lallybroch.
Upon reaching Lallybroch, Claire meets Jamie's sister, Jenny, who is enormously pregnant and has a small child named Jamie, after his uncle. Jamie, thinking that Jenny was raped by Jack Randall several years before, accuses her of standing as the Captain's "doxy," and a terrible fight ensues. Claire escapes from the room and meets Jenny's husband, Jamie's best friend, Ian Murray: the two immediately like one another, and manage to settle their respective spouses down.
Claire becomes fast friends with Jenny, and happily settles into Lallybroch. But Jamie is taken by the Black Watch when out with Ian: Claire, after giving Jenny advice to "plant potatoes" in preparation for the events after Culloden, teams up with Murtagh to try and find where Jamie was taken. Dougal finds them, and informs them that Jamie is in Wentworth Prison awaiting execution. He also reveals his lust for Claire, and offers to marry her after Jamie is dead. Claire of course rejects this, and along with Rupert and Murtagh concocts a plan to rescue him from the prison.
Claire sneaks into the prison and finds Jamie in a small room, already suffering from torture by Jack Randall. She has almost freed Jamie from the room when Randall himself enters with a servant, and holds Claire at knife point; Jamie promises to resist neither Randall's sexual advances nor his torture, in exchange for Claire's freedom. She is thrown out the back door of the castle, and narrowly escapes being eaten by wolves before being rescued by a local Scot, Sir Marcus MacRannoch.
MacRannoch turns out to have been an erstwhile suitor of Jamie's mother, Ellen MacKenzie, and upon Murtagh's and Rupert's arrival, agrees to help rescue Jamie. The Scots release a large herd of cows into the same door through which Claire exited, and in the ensuing stampede Jamie is found and brought unconscious to MacRannoch's house, having been further raped and tortured by Randall.
Claire manages to doctor Jamie's injuries, the worst of which his badly broken hand. They depart for France; between his injuries, being waylaid on the road, suffering through terrible seasickness on the Channel, Jamie is seriously ill by the time they reach the Abbey of Ste. Anne de Beaupré, where his Fraser uncle, Alexander, grants them sanctuary. During Jamie's illness, Claire befriends the Benedictine monk Father Anselm, who counsels her in the religious aspects of marriage: she also confesses her true past to him.
Jamie suffers terribly from the memories of being raped by Jack Randall; he asks Claire to leave him and return to Scotland, since he can't think of her without remembering Randall. But before he can force her to go, Jamie's hand becomes infected. In the subsequent delerium of fever he asks Claire to let him die, which he later admits was because he thought she would amputate the hand. "Damned if I will," Claire says; using opium and the memories of Jack Randall as shock treatment, she brings him through the fever and into convalescance. The novel ends with Jamie recovering from his illness and planning to take Claire to Paris, and her confession that she is pregnant.