The novel begins when a monster, formed from a yew tree, visits thirteen-year-old Conor O'Malley at seven minutes past midnight. Conor has just woken from a recurring nightmare in which his terminally ill mother's hands slip from his grasp. Despite the monster's imposing figure, Conor isn't afraid because it isn't the monster he truly fears—the one that visits him every night in the shape of his recurring nightmare. In the morning Conor believes the monster's visit was another dream, but his bedroom floor is covered in yew leaves.
At school, Conor is bullied by a boy named Harry and two other students. His old friend Lily, who he became alienated from after she told everyone about his mother's diagnosis, steps in to defend him. After Conor refuses to tell the truth about being tripped by Harry, Lily is punished by their teacher, Miss Kwan, for pushing one of the bullies into a shrubbery. That night the monster visits again and tells Conor it will tell three tales, after which Conor must tell his own tale, which will be "the truth."
Conor's grandmother comes to stay when Conor's mother's condition worsens. She says it is important for him to know he has a loving home to go to once Conor's mother dies. Conor has a hostile relationship to his grandmother and denies that they need any extra help at the house. That night, the monster tells Conor the story of a wicked queen and a deceitful heir to the throne. After the heir murders his lover and blames the murder on the queen, the yew tree monster intervenes to protect the queen from the mob of villagers. Conor doesn't understand the point of a story in which both central characters are in the wrong and neither suffers any punishment.
After another encounter with his bullies at school, Conor comes home to learn that his mother's new treatment isn't working and she has to go back to the hospital. His father is also visiting from where he lives with his new wife and daughter in America. Against his wishes, Conor goes to stay at his grandmother's house. For five days the monster doesn't visit and Conor wonders where he is.
When his father arrives, Conor makes fun of the way his father's accent is changing. Conor says he would rather live with his father in the States than stay with his grandmother, but his father says there isn't enough room. Conor returns to his grandmother's angry and breaks her antique clock. The hands stop at 12:07 and the monster appears to tell the story of an apothecary and a parson who got into a dispute when the apothecary wanted to cut down the churchyard yew tree to make remedies. The parson refused and tried to destroy the apothecary's business by badmouthing him in his sermons, but then went to the apothecary for help after his daughters fell ill to an infection modern medicine couldn't cure. The apothecary refused to help someone who was willing to sacrifice everything he believed in. The monster says it destroyed the parson's home and Conor is confused, believing the apothecary was the bad guy. The monster says that neither was particularly good, but the apothecary was at least a healer, while the parson was a person without substance. The monster invites Conor to destroy the parson's house with him, and Conor snaps out of the fantasy to realize he has destroyed his grandmother's sitting room.
His grandmother reacts in anger and despair, but she doesn't punish Conor or acknowledge him. At school Conor feels similarly invisible: only Harry seems to still notice Conor's existance. Conor visits his mother in the hospital and learns that they are going to try a cancer drug made from the bark of a yew tree as a last effort. Conor and his father go for a walk and discuss how Conor's parents haven't been truthful enough with Conor; he says the new treatment is unlikely to work. That night Conor asks the monster if he can heal his mother: the monster answers cryptically, saying that if she can be healed, she will be.
At school the next day, Harry tells Conor that he knows the worst thing he can do to Conor is to no longer see him. Instead of hitting him, Harry turns and walks away, pretending not to hear Conor's voice calling out to him. The monster appears and tells Conor the story of a man who felt invisible and so lashed out in violence to get people's attention. Meanwhile, the monster guides Conor to grab Harry's shirt and punch him repeatedly in the face. Harry is hospitalized and Conor goes to the headmistress's office. Hoping to be punished, Conor is dismayed when the headmistress decides she couldn't punish him given what he is going through with his mother's illness. In class, people notice Conor now but do not interact with him, and he feels further from them than when he was invisible.
Conor is called out of school to see his mother in the hospital. She admits that the yew tree treatment isn't working. He says she lied about believing it would work. She apologizes and says she did want to believe the medicine would work, but she suspects he has always known she wasn't going to get better. At home, Conor confronts the yew tree in the graveyard and demands to know why it didn't heal her. The tree says it is there to heal Conor, not his mother. The tree makes Conor enter the space of his nightmare and admit the truth of how he could have held onto his mother's hands longer but needed to let her go so as to bring about an end, not just to her suffering but to his. The grief burns inside Conor.
Conor wakes on the hill by his house to his grandmother's voice. She rushes him back to the hospital, where the nurse says they aren't too late. Conor holds his mother's hand and, with the monster standing behind him, Conor tells his mother he doesn't want her to go. Conor assures himself that he will make it through her death, which will come soon. No matter how hard he holds onto to her, she will slip. The novel ends with Conor hugging her as a means of finally letting her go.