In 1946, after separation by their work in World War II, British Army nurse Claire Randall and her husband Frank, a history professor, go on a second honeymoon to Inverness, Scotland, where Frank conducts research into his family history and Claire goes plant-gathering near standing stones on the hill of Craigh na Dun. She faints when investigating a buzzing noise near the stones; upon waking, she encounters Frank's ancestor, Captain Jack Randall. Before Captain Randall can take her into his custody, he is knocked unconscious by a Scotsman who takes Claire to his party. When the Scots try to repair the dislocated arm of their comrade Jamie, Claire uses her superior skill to relocate Jamie's arm; whereupon the men identify themselves as members of Clan MacKenzie, and Claire eventually concludes that she has traveled to the past, and represents herself as an English widow who is traveling to France to see her family. The Scots do not believe her and take her to Castle Leoch, where Claire searches for a way to return to her own time.
The Scots of 1743 see Claire as a "Sassenach", an Outlander, ignorant of Scottish Highland culture. Her medical skills earn their respect; but the clan chieftain, Colum MacKenzie, suspects her of being an English spy. Colum sends her with his brother, Dougal, to collect rents and solicits donations for the Jacobites. This is overseen by Ned Gowan, a lawyer from Edinburgh made part of Clan MacKenzie. Captain Randall tells Dougal to bring Claire to him for questioning. To keep Claire from Randall, Dougal tells her to wed Jamie, which she does. Torn between her attachment to Jamie and the thought of Frank, Claire tries to return to Craigh na Dun. When prevented, Claire accepts the position of castle healer, in which she relies on her medical experience, and befriends Geillis Duncan, the wife of a local official, who shares her love of medicine. Eventually Claire and Geillis are charged with witchcraft while Jamie is away, but Jamie returns in time to save Claire. Just before their escape, Claire realizes that Geillis is, like herself, from the future, when she sees a smallpox vaccine scar on Geillis' arm. Geillis also sees Claire's scar.
Claire relates her predicament, and Jamie takes her to Craigh na Dun. When Jamie allows her to decide whether to stay with him or return to Frank, Claire prefers to stay, and Jamie takes her to his home of Lallybroch, where they share a happy peace with Jamie's sister Jenny and her husband, Ian. Though Jamie is still a fugitive from the British army, he reclaims his position as Laird of Lallybroch until one of his tenants betrays him and he is taken to Wentworth Prison, where Captain Randall is stationed. Claire and the clansmen attempt a jail-break, but fail and Claire is captured by Randall, who threatens to have her raped. Jamie offers himself in Claire's place, and Randall ejects Claire into the woods outside the castle. Claire tells Randall that she is a witch and predicts that, after his marriage, he shall father a child, but never see it.
Thereafter Claire is befriended by Sir Marcus MacRannoch, a former suitor of Jamie's mother. While MacRannoch's men distract Wentworth's main guard, the clansmen drive a herd of agitated cattle through the underground halls of the castle, trampling a man. They rescue Jamie, who has been assaulted physically and sexually by Randall, and take him to MacRannoch's stronghold, where Claire tends the worst of Jamie's wounds. As soon as Jamie is capable, they and Jamie's godfather, Murtagh, escape to Saint Anne de Beaupre's monastery in France, where Jamie's uncle is Abbot. As she and Jamie emerge from a sacred hot spring under the Abbey, Claire reveals that she is pregnant.