The novel is set in the town of Comala, considered to be Comala in the Mexican state of Colima.
The story begins with the first person account of Juan Preciado, who promises his mother at her deathbed that he will return to Comala to meet his father, Pedro Páramo. Juan suggests that he did not intend to keep this promise until he was overtaken by visions of his mother. His narration is interspersed with fragments of dialogue from the life of his father, who lived in a time when Comala was a robust, living town, instead of the ghost town it has become. Juan encounters one person after another in Comala, each of whom he perceives to be dead. Midway through the novel, Preciado dies. From this point on most of the stories happen in the time of Pedro Páramo.
Most of the characters in Juan's narration (Dolores Preciado, Eduviges Dyada, Abundio Martínez, Susana San Juan, and Damiana Cisneros) are also presented in an omniscient narration but much less subjectively. The two major competing narrative voices present alternative visions of Comala, one living and one full of the spirits of the dead. The omniscient narration provides details of the life of Pedro Páramo, from his early youthful idealization of Susana San Juan to his rise to power upon his coming of age to his tyrannical abuses and womanizing, and, finally, to his death. Pedro is cruel, and though he raises one of his illegitimate sons, Miguel Páramo (whose mother dies giving birth), Pedro does not love his father (who dies when Pedro is a child) or either of his two wives.
His only love, from a very young age, is that of Susana San Juan, a childhood friend who leaves Comala with her father at a young age. Pedro Páramo bases all of his decisions on, and puts all of his attention into trying to get Susana San Juan to return to Comala. When she finally does, Pedro makes her his, but she constantly mourns her dead husband Florencio and spends her time sleeping and dreaming about him. Pedro realizes that Susana San Juan belongs to a different world that he will never understand.
When she dies the church bells toll incessantly, provoking a fiesta in Comala. Pedro buries his only true love, and angry at the indifference of the town, swears vengeance. As the most politically and economically influential person in the town, Pedro crosses his arms and refuses to continue working, and the town dies of hunger. This is why in Juan's narration, we see a dead, dry Comala instead of the luscious place it was when Pedro Páramo was a boy.