My Brilliant Friend by Elena Ferrante is the first instalment of a 4-novel series. It starts off the story when Elena Greco, the protagonist and narrator, receives a phone call from her old friend Lila Cerullo's son Rino. He calls to tell Elena, who is now an elderly woman, that Lila has disappeared. This is the introduction that starts the action of the novel as Elena retells the story of her friendship with Lila, starting from when they were young girls.

Elena and Lila grew up together in an impoverished town and went to school together. Elena is a studious and focused girl, and she is inspired and threatened Lila because of her natural intelligence and her ability to get good grades seemingly without trying. Although the other children at school do not like Lila, her and Elena form a close bond. One day Lila throws Elena's doll into the cellar of the town maniac, Don Achille. Elena feels the peer pressure and follows suit, throwing Lila's doll into the cellar as well.

As they grow up they witness the murder of Don Achille and they both attend middle school due to their academic success, despite Lila's parents' wish that she continue into a more technical field. Elena grows more jealous of Lila's charisma as they grow older and more boys and men become interested in Lila. Lila's father owns a shoe store, and she has dreams that her family eventually sells their own brand of shoes. Her and her brother Rino design their own shoes without telling their father.

Marcello Solara is one of those boys, and he begins to visit Lila's father's shoe store regularly to see her and get her father's approval to marry her, which he receives despite Lila's disregard for him. Meanwhile Elena is pursued by Nino Sarratore at the seaside where they both spend their summer. In August his father Donato sexually assaults Elena after she has gone to bed, and she runs back to her family and Lila in Naples the next day.

That fall, Stefano Carracci proposes to Lila and she accepts. His family is wealthy and influential and so Lila begins to enjoy his lifestyle while they are engaged. As usual, Elena is jealous of Lila but is still a supportive friend as she feels she needs to be. She even acts as a mediator for Lila and Stefano's family members who have left their jobs to dedicate all their time to wedding planning.

The novel ends at the wedding between Lila and Stefano. Elena is unhappy at the wedding because there is tension between her boyfriend Antonio and former lover Nino. Lila notices that Marcello arrives at the wedding wearing the first ever pair of shoes she had ever designed, even though they had originally been bought by Stefano. Lila sees this as a betrayal, and believes her marriage is doomed before it has even begun. The novel ends with no real resolution, urging the reader to wait for the next instalment to find out what happens to Elena and Lila, and what eventually has led to Lila's disappearance.