During World War II, Claire Randall, a British Army nurse, and her husband Frank, an Oxford University History professor, work for MI6. In 1946, after the war ends, they visit Inverness, Scotland, the site of their wedding before the war. They combine their second honeymoon with research into his family history, investigating an ancestor named "Black Jack" Randall, a Captain in the British Army, in the first half of the 18th century.
During their holiday, her husband meets with another historian while she and an amateur botanist go plant-gathering near a group of standing stones on the hill of Craigh na Dun. Claire tells Frank of her visit to Craigh na Dun and, Frank's interest piqued by the historical and supposedly mystical powers of the stones, the two decide to visit the site again after seeing Loch Ness. When Frank learns that a group of local women, including the local vicar's housekeeper, will enact a pagan ritual there, he is all the more eager to go. Claire, a budding botanist, is particularly captivated by the flowers and herbs she finds, although the unusual ritual is also of interest to her. After getting up early, hiking to the stones, and watching the ritual concealed behind some bushes, Frank and Claire return to their hotel.
Claire returns the next day, intending to collect a plant specimen that she had seen the day before, but becomes disoriented and faints when investigating a buzzing noise near the stones. Waking to the sound of battle in the distance, Claire assumes it is a re-enactment or a movie set, taking a detour through woods that, though familiar, have changed somewhat from how she remembered them.
Struggling to make sense of her surroundings, she runs into a man claiming to be Captain "Black Jack" Randall, the very ancestor with whom Frank was so fascinated, who looks almost exactly like Claire's husband. Detaining her, he asks her why she is traveling alone in a "state of undress" and, receiving no answer from a vastly confused Claire, and concludes that she is either a prostitute or a spy. Retrieving her wits, Claire claims to be robbed Englishwoman lost in the countryside. She is saved from capture by a skeptical Randall by an unknown Scotsman who, knocks Captain Randall unconscious and takes her with him to he rejoins his party, a group to Scotsmen who are on the run from the red-coats after rustling cattle. Still confused, she doesn't understand the situation, her "re-enactment" theory dissipating, and is further puzzled by their reactions to her dress, which everyone calls a "shift" because her legs are bare.
Upon seeing that his companions were about to force the dislocated shoulder of one of the men back into place, an action that could have crippled him, Claire mends his dislocation using her nursing experience and 20th century medical knowledge. Claire meets several members of the Clan MacKenzie, and decides that their "costumes" and weapons are just too realistic. Concluding they cannot let her go for fear that she is an English spy, they force her to travel on horseback with them through the Scottish countryside. During a long ride, Claire shares a horse with the same young man whose arm she healed, Jamie. While the they ride, not seeing the lights of Inverness where she knows they must be and noting all the previous strange events, Claire reluctantly concludes that she may have traveled to the past.
The party of Scots return to their home, Castle Leoch, seat of the Clan MacKenzie. She is met with cordial wariness and, after being greeted and fed by the friendly cook, given a room for the night. There, caught by a fit of despair and exhaustion while tending his injuries, Claire collapses and sobs in Jamie's arms.
The next day, when questioned by the laird, crippled but cunning Colum mac Campbell MacKenzie, Claire claims she was sailing to France to visit relatives and lost her gown, luggage, and servant when they were attacked, an elaborated version of the same story she had told Captain Randall. The Scots are suspicious, believing her story to be a lie because of her lack of connections and evidence. Unable to prove her guilt but still wary of her true intentions, Colum treats her as a guest but forbids her from leaving Castle Leoch. Before she leaves his office, her fears of having traveled through time are proven when she sees a letter on Colum's desk dated 1743.
All the while, Claire desperately searches for a way to return to the Craigh na Dun, believing that if she returns to the standing stones she can also return to her own time and her husband, Frank. In Castle Leoch, The Scots see Claire as a "Sassenach", an Outlander, an outsider ignorant of Scottish Highland culture and one of the generally hated English as well. She does, however, earn their respect with her work as a healer, though some in the castle and neighboring village think her a witch. Wanting to learn the truth of her background, Dougal MacKenzie, brother of the laird and part of the party that found Claire, takes both her and Jamie on the yearly rent collection through the MacKenzie lands. This is a task Dougal performs as Colum's medical condition renders him unable to ride a horse or travel long distances unaided.
While on the tax collection trip, Claire realizes that Dougal is a Jacobite, a fact of which his brother Colum is not aware, and is using Jamie, who had been violently whipped by the English and bears the scars to prove it, to be a visual argument against English aggression and oppression. Along with the regular taxes, Dougal also collects donations towards the Jacobite cause. This is all overseen by the elderly but surprisingly lucid Ned Gowan, an English lawyer who is sympathetic to the Scottish cause. Also during the trip, Claire and Jamie begin to develop a tentative friendship.
Captain Jack Randall, learning that Claire is travelling with the MacKenzies and still unsure of her true nature, orders the clansmen to bring her to him. It is revealed that Randall is the one who had ordered Jamie to be whipped half to death and has a reputation for rather brutal questioning. After Claire arrives and tells him the same story as before, Randall ties her to a chair and attempts to beat the truth from her. Dougal, infuriated by Randall's methods, refuses to allow Randall to detain Claire for further questioning. He is informed by Ned Gowan that the only way to make Claire safe from Randall's power is to make her a legal Scotswoman by a witnessed and consummated marriage. Dougal tells her to wed Jamie, much to Claire's flustered anger. She argues heatedly with Dougal, insisting that she will not do it. Claire does, however, digress that she is not technically married, unable to tell him that she, impossibly, has a husband more than 200 years in the future. After much argument, she agrees to marry Jamie, resigned that it is the best route to safety and thinking him the most suitable candidate.
Claire then attempts to convince Jamie out of the marriage though he is surprisingly unfazed by the whole arrangement. She famously asks him whether it bothers him that she is not a virgin, to which he replies "'Well no... so long as it doesna bother you that I am'" and that "'One of [them] should know what they're doing.'"
Much to her surprise, Jamie makes an effort to make her wedding day as pleasant as possible, procuring a gown for her to wear and dressing in full clan tartan for the occasion. He even insists on being married by a priest in a chapel, though it is, much to Claire's horror, the same one in which she and Frank had/will have been married in. Claire, though terrified, is touched at his kindness and the two marry. Later that night, the two overcome their mutual nerves and consummate their marriage, a process Claire finds more pleasant than she had expected.
Claire and Jamie grow closer through the course of their travels with Dougal and the other MacKenzies. Claire, torn between her newfound attraction and attachment to Jamie and the thought of Frank back in her own time, escapes from the Scottish party and attempts make her own way back to Craigh na Dun. Nearly drowning when she falls into a stream, she is rescued by an English patrol only to brought back to the fort where Jack Randall is residing. Claire is saved from rape at the hands of Randall by Jamie, who sneaks into the English fortress to save her. The two return to the party of Scotsmen who, all furious at her actions, refuse to have any contact with her.
Jamie reveals to Claire that his rescue mission was firmly opposed by
Claire's healing skills as a 20th century nurse save Jamie repeatedly but as the story progresses, she is determined to return to the stone circle and Frank, knowing he must be worried sick. As life continues at Castle Leoch, Claire's marriage to Jamie, ignorance of local superstition, and jealousy towards her lead to a charge of witchcraft. Thrown into a hole with another accused witch, Geilie Duncan, to await trial, she is rescued by Jamie. Just before her escape, she realizes that Geilie Duncan is from the future too. When Jamie asks her to explain, she initially tells him she can't as he won't believe her, saying it's easier to call her a witch.
Shocked by Claire's explanation, he takes her to the stone circle and tells her to return to Frank - seeing for himself, that Claire is telling the truth about the stones. Jamie leaves her there to decide if she wants to return to Frank or stay with him. He is over the moon with her decision to stay and he takes her to his home, Lallybroch, but their happiness doesn't last.
Jamie has a price on his head and is betrayed by Ronald McNab, one of his tenants. Angry that Jamie, after being told by Claire and Grannie McNab of Ronald's abuse of the child, insists Rabbie become a stable-boy at Lallybroch. Jamie is held at Wentworth Prison and sentenced to hang. Sadistic Jack Randall is also at Wentworth and takes the opportunity to torture Jamie. Jamie, however, promises Jack that he'll sleep with him if he lets Claire go. Jack agrees and in revenge, Claire tells Jack she is a witch, cursing him with the "gift" of knowledge that he will marry and have a son but will die before the child's born, giving him the date of his death.
Aided by Sir Marcus MacRannoch, a former suitor of Jamie's mother, Ellen MacKenzie Fraser, Claire, Jamie's relatives and men employed by Sir Marcus, rescue Jamie. She patches him up and they escape to Ste. Anne de Beaupre's monastery in France, where Jamie's uncle is stationed as Abbot. At Ste. Anne's, Claire tries healing Jamie, but discovers broken bones are simple, compared to repairing the damage done to his mind. As he recovers, Jamie tells Claire that his life is hers, that she should decide, will they go "to France, Italy, or even back to Scotland?" for "[they'll] need a place to go, soon."
Whilst at the abbey, Claire learns more about her faith - she was christened Catholic but not raised as one - and receives absolution from a friendly monk. He describes her as a shipwrecked traveller, forced to survive in a strange land as best she can. He describes her marriages as something she should leave in God's hands as nothing can be done about them. At the last, as she and Jaime emerge from the healing waters of a sacred hot spring under the Abbey, Claire reveals that she is pregnant with their first child