The non-linear story, told by an anonymous narrator, begins with 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 Arabic origin. He returns home in the early morning hours from an all night celebration of a wedding between a recent newcomer, Bayardo San Roman, and a long-term resident, Angela Vicario. Two hours after the wedding, Angela was dragged back to her mother's home by Bayardo because she was not a virgin. After a beating from her mother, Angela 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. Her two twin brothers, Pablo and Pedro Vicario, decide to kill Santiago in order to avenge the insult to their family honor with two knives previously used to slaughter pigs.
They 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 the brothers are such "good people", or they interpret the threat as "drunkards' baloney". 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 takes away their knives and sends them off to sleep though he considers them "a pair of big bluffers". Clotilde wants "to spare those poor boys from the horrible duty" and tries to convince Colonel Aponte to investigate further so they can be stopped. He does nothing more. Since the brothers had announced their plans to kill Santiago at the meat market and the milk store, the news spreads through town, but no one directly warns Santiago. Clotilde asks everyone she sees to warn Santiago, but people do not warn him for several reasons: they assume he must have been warned already, believe that someone else should warn him, can't find him easily, don't believe it will happen, are too excited about the Bishop's arrival, want him secretly dead, or believe the killing to be justified. The brothers show up again to the milk shop with two new knives, and this time Pedro has hesitations about killing because he feels they had fulfilled their duty "when the mayor disarmed them". Nevertheless, they yell their plans to kill Santiago. Even the priest later confesses, "I didn't know what to do...it wasn't any business of mine but something for the civil authorities." He decides to mention it to Santiago's mother, but because he was excited about the bishop coming, he forgets about Santiago.
Santiago wakes up after an hour's sleep to get dressed and greet the bishop, who is expected by the townsfolk to stop in their town on his way elsewhere. He misses the note on the floor that someone has left with a warning and details about the Vicario plan. 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 Angela Vicario and decides not to warn him.
The murder occurs. 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 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 Angela does she 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 returns to her, carrying all of her letters in bundles, all unopened.
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.