The book is a nonlinear narrative told by an anonymous narrator and begins on the morning of Santiago Nasar's death. 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, who was of Arab origin. He returns home in the early morning hours from an all-night celebration of a wedding between a recent newcomer, Bayardo San Román, and a long-term resident, Ángela Vicario. Two hours after the wedding, Ángela was dragged back to her mother's home by Bayardo because she was not a virgin. After a beating from her mother, Ángela is forced to reveal the name of the man who has defiled her purity and honor. In a somewhat spurious manner, she reveals the man to be Santiago. To avenge their family honor, her twin brothers Pablo and Pedro Vicario decide to kill Santiago using knives that they'd previously used to slaughter pigs.
The brothers proceed to the meat market in the pre-dawn hours to sharpen their knives and announce to the owner and other butchers that they plan to kill Santiago. No one believes the threat because Pablo and Pedro are considered "good people", and most interpret their threats as drunken rambling. Faustino Santos, a butcher friend, becomes suspicious and reports the threat to the policeman, Leandro Pornoy. The brothers proceed to Clotilde Armenta's milk shop where they tell her about the plan to kill Santiago, and she notices the knives wrapped in rags. Meanwhile, Officer Leandro talks with Colonel Aponte who, after leisurely dressing and enjoying his breakfast, proceeds to the milk shop and confiscates the brothers' knives, sending them off to sleep and calling them "a pair of big bluffers". Clotilde is still concerned that the twins will find another way to carry out their plan to murder Santiago and urges Colonel Aponte to intervene further "to spare those poor boys from the horrible duty", but he does nothing more.
Gossip about the twins' publicly announced plans spreads through the town, and though Clotilde asks everyone she sees to warn Santiago, no one does. Some do not believe they should get involved, some assume that he has already been warned, some believe the twins wouldn't really follow through, some are distracted by the arrival of the Bishop, some believe that the murder would be justified, and some secretly want Santiago dead. As the priest later confessed, "I didn't know what to do... it wasn't any business of mine but something for the civil authorities."
The brothers return to the milk shop wielding new knives, and this time Pedro expresses hesitation about their plan because he feels they had fulfilled their duty "when the mayor disarmed them". Nevertheless, they repeat their intention to kill Santiago. Santiago wakes up after an hour's sleep to get dressed and greet the bishop along with many of the townsfolk, who expect him to stop in their town while traveling elsewhere. As Santiago leaves, he does not notice the note that someone had left to warn him about the Vicario brothers' threats on his life. The bishop's boat passes by the town without stopping even though people have been waiting for him with various gifts. Santiago then proceeds to his fiancée, who yells, "...I hope they kill you!" because she is upset about his involvement with Ángela Vicario and decides not to warn him.
The murder of Santiago Nasar is described. His 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 minutes before the twins reach Santiago. Santiago becomes disoriented from the news and starts to run home. His mother, who is finally told, believes he is inside the house and, therefore, bars the front door to which Santiago is running while being chased by the Vicario brothers. He is repeatedly stabbed as he attempts to enter his home, over twenty times total with seven fatal wounds, as they discovered in an ill-performed autopsy performed by the priest. The murder is brutal as Santiago carries his own entrails and enters the back door of his home. He collapses in his kitchen and dies.
After the murder, the Vicario family leaves town due to the scandal and disgrace surrounding the events of Ángela's wedding and Santiago's murder. Bayardo San Román leaves town as well; his family comes by boat and picks him up. The Vicario twins spend three years in prison awaiting trial but are acquitted in court, after which Pablo marries his lover and Pedro leaves for the armed forces.
Only after Bayardo rejects Ángela does she fall in love with him. After she moves away from the town with her family, Ángela writes him a letter each week for seventeen years. At the end of seventeen years, Bayardo returns to her, carrying all of her letters in bundles, all unopened.
