The central character, Melmoth (a Wandering Jew type), is a scholar who sells his soul to the devil in exchange for 150 extra years of life; he spends that time searching for someone who will take over the pact for him. The novel takes place in the present but the backstory is revealed through several nested stories-within-a-story that work backwards through time.
Chapter I: The story opens in 1816: John Melmoth, a student in Dublin, visits his dying uncle. He sees a portrait of his namesake dated '1646' and catches glimpse of 'the Traveller'.
Chapter II: Funeral. Biddy Brannigan tells John the family story. A stranger called Stanton arrived looking for the Traveller, and left behind a manuscript. John finds Stanton's manuscript.
Chapter III: Stanton's story opens in Spain in the 1670s. Stanton encounters the Traveller laughing at the sight of two lovers who have been blasted by lightning. An old Spanish woman tells him the story of the Cardoza wedding at which the Traveller was an uninvited guest. The bride died on her wedding night and the bridegroom went mad. Stanton pursues and finds the Traveller in a theatre in London. The Traveller tells him they will meet again. Stanton's obsession with the Traveller is judged madness and he is tricked into a madhouse. There, the Traveller appears and offers to free him but Stanton refuses. Stanton escapes and looks for him in Ireland to no avail. Following his uncle's wish, John burns the portrait, but later that night he is visited by his ancestor in his dreams.
Chapter IV: The following stormy night, John witnesses the Traveller laughing at a shipwreck. John tries to approach him, but slips and falls into the sea.
Chapter V: John is saved from drowning bye the sole survivor of the wreck, a Spaniard Alonzo Monçada, who begins to tell him his story.
Chapter VI: Monçada continues his story. He is confined unwillingly to a monastery by his family.
Chapter VII: Monçada continues his story. His appeal to leave the monastery is rejected and his brother Juan sends messages saying he will help him escape.
Chapter VIII: Monçada continues his story. He attempts to escape with the help of a fellow monk, a parricide.
Chapter IX: Monçada continues his story. The parricide monk tells his story. They escape, but it is a trap and Monçada's brother is killed.
Chapter X: Monçada continues his story. Monçada is held and examined in the prison of the Inquisition.
Chapter XI: Monçada continues his story. He is visited in his cell by the Traveller, who says he will help him escape. A fire breaks out, the prison is evacuated and in the confusion Monçada escapes.
Chapter XII: Monçada continues his story. He finds his way to the house of a Jew, but officers of the Inquisition arrive searching for him. The Jew helps Monçada escape through a secret trapdoor into an underground passage.
Chapter XIII: Monçada continues his story. He finds himself in a secret chamber with a venerable Jewish scholar, Adonijah. The chamber is decorated with the skeletons of members of Adonijah's family.
Chapter XIV: Monçada continues his story. Monçada is almost out of his mind with terror, but Adonijah gives him food and drink, and says he must transcribe a certain manuscript for him. This contains The Tale of the Indians: an island in the Indies which has been devastated and depopulated by a storm is said to be haunted by a white goddess. A pair of Indian lovers discover the white goddess on the island and worship her. (The story is announced as 'The Tale of the Indians', but at its conclusion this is altered to 'The Tale of the Indian'.)
Chapter XV: Monçada's story: The Tale of the Indians. Immalee, the name the natives have given to the 'white goddess', encounters the Traveller. He tells her he comes from 'the world that suffers', but she is immediately fascinated by him.
Chapter XVI: Monçada's story: The Tale of the Indians continues. Immalee is again visited by the Traveller who starts to try to destroy her innocence, showing her the shortcomings of various religions. Immalee decides she will be a Christian.
Chapter XVII: Monçada's story: The Tale of the Indians continues. The Traveller returns and shows Immalee the failings of human societies and human relationships. Immalee despairs of her love for him.
Chapter XVIII: Monçada's story: The Tale of the Indians continues. The Traveller returns and continues with his attempts to corrupt Immalee. She reiterates her love for him and begs him to stay with her and not to go back to his world of 'evil and sorrow', but he will not.
Chapter XVIII: Monçada's story: The Tale of the Indians continues. During a great storm, the Traveller and Immalee reach a crisis in their relationship. She falls senseless to the ground and the Traveller departs.
Chapter XIX: Monçada's story: The Tale of the Indians continues. Three years later in Spain: a young woman faints at the sight of a stranger (Immalee and the Traveller).
Chapter XX: Monçada's story: The Tale of the Indians continues. The long-lost Immalee, now Isidora, has been restored to her family in Madrid. Melmoth appears beneath her window and once more attempts to seduce her.
Chapter XXI: Monçada's story: The Tale of the Indians continues. Melmoth continues to appear beneath Isidora's window, but loses patience and renounces her.
Chapter XXII: Monçada's story: The Tale of the Indians continues. Isidora is sanguine, knowing Melmoth will not abandon her for long. Isidora's father writes to her mother revealing he has found a husband for his daughter: Isidora and Melmoth plan to elope.
Chapter XXIII: Monçada's story: The Tale of the Indians continues. Isidora's father is visited by his daughter in a dream, asking him to save her.
Chapter XXIV: Monçada's story: The Tale of the Indians continues. Isidora and Melmoth elope by night, and he leads her to a remote chapel where they are married by a mysterious hermit, whose hand was 'as cold as that of death' (in a later chapter it is revealed that the hermit was already dead).
Chapter XXV: Monçada's story: The Tale of the Indians continues. Isidora's father, traveling home, catches a glimpse of the Traveller, and encounters a stranger at an inn who tells him 'The Tale of Guzman's Family'.
Chapter XXVI: Monçada's story: The Tale of the Indians - 'The Tale of Guzman's Family'. Guzman. a wealthy Spanish merchant, has a younger sister who marries a poor German musician, Walberg. Guzman decides to make them his heirs and brings them and their children, and Walberg's parents back to Spain.
Chapter XXVII: Monçada's story: The Tale of the Indians - 'The Tale of Guzman's Family'. The Walberg family have got used to living in style and comfort when Guzman dies. His Will leaves everything to the church. A friendly priest tries to help them but the case is thrown out of court.
Chapter XXVIII: Monçada's story: The Tale of the Indians - 'The Tale of Guzman's Family'. The family sinks into desperate poverty, the grandmother dies, the son sells his blood, the daughter almost becomes a prostitute. At last, almost insane, Walberg decides to end it by killing them all, and thinks he has, when news arrives that the true Will has been found and the family is saved. Isidora's father falls asleep and wakes to find the teller of the Tale replaced by the Traveller. The Traveller shows him the corpse of the story-teller.
Chapter XXIX: Monçada's story: The Tale of the Indians. Isidora's father continues his journey, but again encounters the Traveller who tells him 'The Lovers' Tale', about the three grandchildren of Sir Roger Mortimer: Margaret (Sir Roger's heir), Elinor and John.
Chapter XXX: Monçada's story: The Tale of the Indians - 'The Lovers' Tale' continued. Elinor and John fall in love, but John jilts her at the altar, and Elinor flees to Yorkshire. Elinor returns to live near Margaret and John, hoping to regain his affections, but he remains strangely aloof.
Chapter XXXI: Monçada's story: The Tale of the Indians - 'The Lovers' Tale' continued. Elinor sees the hopelessness of her situation and returns to Yorkshire. Margaret marries John.
Chapter XXXII: Monçada's story: The Tale of the Indians - 'The Lovers' Tale' continued. Margaret dies in childbirth and John's mother confesses she invented a story that Elinor and John are brother and sister. John becomes insane with grief, and Elinor takes care of him. Elinor is tempted by Melmoth the Traveller, but turns to a local clergyman for help. John dies, and soon after Elinor also.
Chapter XXXIII: Monçada's story: The Tale of the Indians. Isidora's father complains about the length of the Tale. The Traveller then tells him the tale of Isidora and her father, urging him to save his daughter. But Isidora's father, strangely distracted, is called away on business to another part of Spain.
Chapter XXXIV: Monçada's story: The Tale of the Indians. Isidora is discovered returned to her family, but she is secretly pregnant with Melmoth's child. She has a presentiment that she will not live, and gets Melmoth to promise the child will be brought up a Christian.
Chapter XXXV: Monçada's story: The Tale of the Indians. Isidora's father returns home with the bridegroom. In the middle of the wedding celebrations Melmoth appears and tries to abduct Isidora. Her brother tries to intervene and is killed. Isidora falls senseless and Melmoth the Wanderer escapes.
Chapter XXXVI: Monçada's story: The Tale of the Indians. Isidora reveals she is married. She gives birth to a daughter. Isidora and her baby are taken away by the Inquisition.
Chapter XXXVII: Monçada's story: The Tale of the Indian(s) concluded. Isidora is examined by the Inquisition. They cannot break her so threaten to take away her child. When they come for the child they find it is dead. Isidora, herself dying of grief, remembers her island paradise. She asks if 'he' will be in the heavenly paradise.
Chapter XXXVIII: Monçada tells John that he will relate the story of Adonijah's family, but they are interrupted by the appearance of the Wanderer. He confesses to them his purpose on Earth, and that he has never been successful in tempting another into damnation. 'I have traversed the world in the search, and no one to gain that world, would lose his own soul!' The Wanderer sleeps and has a vision of his own damnation, and of the salvation of Stanton, Walberg, Elinor, Isidora and Monçada.
Chapter XXXIX: John and Monçada approach the Wanderer the next morning, but he asks them to leave him alone for his last few hours of mortal existence. They hear terrible noises coming from the room, but when they again enter, it is empty. They follow the Wanderer's tracks to the top of a cliff. They see his handkerchief on a crag below them, and, 'exchanging looks of silent and unutterable horror', return slowly home.