The narrative outlines the events surrounding the murder of Santiago Nasar, a young man who is thought to have taken the virginity of Angela Vicario. On her wedding night, after discovering that she was not a virgin, Angela's husband, Bayardo San Roman, returns her to her house. Angela's twin brothers, Pedro Vicario and Pablo Vicario, ask her who took her virginity, and she tells them that Santiago Nasar did. The brothers find Santiago and kill him.

The narrative is non-linear. The narrator begins the story by telling us about Santiago Nasar's household the morning he was murdered. In the course of the chapter, we learn that Santiago lived with his mother, Placida Linero; their cook, Victoria Guzman; and her daughter, Divina Flor. Santiago's father, Ibrahim Nasar, has died three years previously. After his father died, Santiago took over the family ranch, which has been very successful; the Nasars are wealthy in their community.

The day that Santiago is murdered was a significant day in town because the Bishop was coming by boat to bless the marriage of Angela Vicario and Bayardo San Roman. Many people were heading over to the dock to see the boats. Pedro and Pablo Vicario were sitting in the local milk-shop, which was en route to the dock, so that they could see Santiago Nasar either going or returning in order to track him down and kill him. The narrator's sister learns that Angela Vicario was returned home on the night of her wedding.

Bayardo San Roman had come to town to find a bride. After deciding on Angela, the courtship was short. Because Bayardo came from a prestigious, wealthy family, and the Vicarios were relatively poor, Angela did not really have a choice, even though she did not love Bayardo at the time they were wed.

The night before the murder, there had been lots of wedding revelry that had continued into the early morning at a local whorehouse run by Maria Alejandrina Cervantes, where Santiago Nasar had been carousing with the twins and the narrator until early in the morning. After returning home and finding their sister in disgrace, the Vicario brothers set out to avenge her honor by murdering Santiago Nasar. Even though they repeatedly announced their intent to murder him, the butcher, the police officer, and the Colonel all thought that the Vicarios are largely bluffing. Clothilde Armenta, the proprietor of the milk shop, even told the local priest about what the Vicario twins were threatening to do. However, in the excitement surrounding the arrival of the bishop, he forgot about her warning.

After the murder, the entire Vicario family left town because of the disgrace the combination of events had brought upon their family. A week after the murder, Bayardo San Roman left with his family; they came and retrieved him by boat. The Vicario brothers were imprisoned for three years. After their release from prison, Pablo proceeded to marry his betrothed, Prudencia Cotes, and Pedro went back into the armed forces.

After Bayardo returned Angela to her home on their wedding night, she fell in love with him. After she moved away from the town where she was disgraced, she wrote him letters every week for seventeen years, and eventually he returned to her.

For years after the crime, it was all anyone in the town spoke of. The narrator tells how his friend Cristo Bedoya searched frantically for Santiago the morning of the murder in order to warn him of the Vicario brothers' plan, but failed to find Santiago because he did not realize that Santiago had gone to the house of his fiance, Flora Miguel. Her father was the first to warn Santiago of the murder. At this point, there were crowds of people outside who had come to see the Bishop but had lingered because they had heard the rumor that Santiago was to be killed.

When he left Flora Miguel's house, Santiago was very confused. Clothilde Armenta yelled at him to run, and he ran the fifty yards to his front door. The Vicario brothers easily caught up with him, and stabbed him to death right outside of Santiago's front door.