The non-linear story, told by an anonymous narrator, begins with the morning of Santiago Nasar's death. He wakes up from an ostensibly meaningless dream of trees. The reader learns that Santiago lives with his mother, Placida Linero; the cook, Victoria Guzman; and the cook's daughter, Divina Flor. Santiago took over the successful family ranch after the death of his father Ibrahim.
The day of Santiago Nasar's death also happens to be the day the Bishop plans to come by boat to bless the marriage of Angela Vicario and Bayardo San Roman. His blessings, as the reader learns later, will be of no use. As the town prepares for the Bishop's arrival, Angela's twin brothers Pedro and Pablo sit in the local milk shop watching for Santiago so that they may carry out their plans to murder him.
The reader gradually learns of Angela Vicario's story: her groom, Bayardo San Roman, was a foreigner who had come to town to find a bride. After finding Angela, Bayardo decided to marry her; his wealthy status compared with the relative poverty of the Vicarios left no choice for Angela's freedom, and thus they were planned to wed.
The night before the wedding day, festivities in preparation for the wedding took place at a local whorehouse run by Maria Alejandrina Cervantes, where the narrator partied with Santiago and the Vicario twins until the early morning. The Vicario twins left and returned home to find that their sister had been quietly returned by Bayardo San Roman, who had found out that she was not a virgin as he had expected. When asked who deflowered her, Angela Vicario says that it was Santiago Nasar. Thus the twins, in the wake of their family's disgrace, began planning their murderous revenge.
Once morning arrives, the twins set about town, repeatedly announcing their plans to everyone who will listen. Yet despite the fact that nearly the whole town is aware of the planned murder before it occurs, no one warns Santiago, because they cannot find him, they don't believe the twins, they are too excited about the Bishop's arrival, they expect others to inform him, or, in some cases, because they encourage the twins to go through with it. Clotilde Armenta attempts to persuade the mayor, Colonel Aponte, but finds herself ignored; he confiscates the knives they were carrying but lets them go, after which they retrieve a second set.
The murder occurs (and is only elaborated upon at the end of the book). After the murder, the Vicario family leaves town due to the scandal and disgrace surrounding the events of Angela's wedding and Santiago's murder. Bayardo San Roman leaves town as well; his family comes by boat and picks him up. The Vicario twins are imprisoned for three years, after which Pablo marries his lover and Pedro leaves for the armed forces.
The reader discovers that only after Bayardo returned her did Angela fall in love with him. After she moves away from the town with her family, Angela writes him a letter each day for seventeen years. At the end of seventeen years, Bayardo San Roman returns to her, carrying all of her letters in bundles, all unopened.
The narrator ends the book with the story of the actual murder of Santiago Nasar. Their friend Cristo Bedoya had frantically looked for Santiago on the morning of the murder to warn him of the plan, but Cristo Bedoya failed to find Santiago, who was actually at his fiancée Flora Miguel's house. When Flora Miguel's father finds out, he warns Santiago seconds before the twins reach Santiago. Santiago only comprehends what Flora Miguel's father is saying as he dies, stabbed outside his own front door.