Jamaica Inn tells the story of 23-year-old Mary Yellan, who was brought up on a farm in Helford. After her mother's death, Mary goes to live with her only surviving relative, her mother's sister, Patience, at the Jamaica Inn. Patience's husband, Joss Merlyn, is a local bully, stands almost seven feet tall and is a drunk. On arriving at the gloomy and threatening inn, Mary finds her aunt in a ghost-like state under the thumb of the vicious Joss, and soon realises that something unusual is afoot at the inn, which has no guests and is never open to the public. She tries to squeeze the truth out of her uncle during one of his benders, but he tells her, "I'm not drunk enough to tell you why I live in this God-forgotten spot, and why I'm the landlord of Jamaica Inn."
Against her better judgement, Mary becomes attracted to Joss's younger brother, Jem, a petty thief, but less brutal than his big brother. After Mary realises that Joss is the leader of a band of wreckers and even overhears Joss ordering the murder of one of their members, she is unsure whether to trust Jem or not. She turns to Francis Davey, the albino vicar of the neighbouring village of Altarnun, who happened to find Mary when she got lost one day on the moor.
Mary and Jem leave the moors for Christmas Eve and spend a day together in the town of Launceston, during which Jem sells a horse he stole from Squire Bassat back to the squire's unwitting wife. When it comes time to return to Jamaica Inn, Jem leaves Mary to get the jingle, but never returns. Mary has no way to get home except by walking, but when she attempts this realises the weather and distance make it impossible. At this point Francis Davey passes her on the road in a hired coach and offers her a lift home. He leaves the coach at the crossroads to walk to Altarnun. The coach is then waylaid by her uncle's band of wreckers, and the coach driver is killed. Mary is forced to go along with the wreckers and has to watch as they 'wreck' - tricking a ship into steering itself on to the rocks and then murdering the survivors of the shipwreck as they swim ashore.
A few days later, Jem comes to speak with Mary, who is locked in her room at the inn. With Jem's help, Mary escapes and goes to Altarnun to tell the vicar about Joss's misdeeds, but he isn't at home. She then goes to the squire's home and tells his wife her story, but Mrs Bassat tells Mary that her husband already has the evidence to arrest Joss and has gone to do so. Mrs Bassat has her driver take Mary to Jamaica Inn, where they arrive before the Squire's party. Mary goes inside and finds her uncle stabbed to death; the squire and his men arrive soon thereafter and discover Aunt Patience similarly murdered.
The vicar arrives at the inn, having received a note Mary left for him that afternoon, and offers her refuge for the night. The next day, Mary finds a drawing by the vicar; she is shocked to see that he has drawn himself as a wolf while the members of his congregation have heads of sheep. The vicar returns and tells Mary that Jem was the one who informed on Joss. However, when he realizes that she has seen the drawing, the vicar reveals that he was the true head of the wrecker gang and responsible for the murderers of Joss and Patience. He then flees the vicarage, taking Mary as his hostage. The vicar explains that he sought enlightenment in the Christian Church but did not find it, and instead found it in the practices of the ancient Druids. As they flee across the moor to try to reach a ship to sail to Spain, Squire Bassat and Jem lead a search party that closes the gap, eventually coming close enough for Jem to shoot the vicar and rescue Mary.
Mary has an offer to work as a servant for the Bassats, but instead plans to return to Helford. One day as she walks on the moor, she comes across Jem, leading a cart with all of his possessions, headed in the opposite direction of Helford. After some discussion, Mary decides to abandon her plans to return to Helford to go with Jem.