The Goldfinch is told in retrospective first-person narration by Theodore "Theo" Decker. As a thirteen-year-old boy, Theo's life is turned upside down when he and his mother visit the Metropolitan Museum of Art to see an exhibition of Dutch masterpieces, including a favorite painting of hers, Carel Fabritius' The Goldfinch. There, he becomes intrigued by a red-headed girl with an elderly man. A bomb explodes in the museum, killing his mother and several other visitors.

In the rubble, Theo encounters the old man who gives him a ring and delivers an enigmatic message before dying. Believing that the man is pointing at The Goldfinch, Theo takes it during his panicked escape. He moves in with a school friend, Andy Barbour, and his wealthy family in their Park Avenue apartment. He carries out the old man's last wishes and returns the ring to his business partner, James "Hobie" Hobart. Theo learns that the old man's name was Welton "Welty" Blackwell, and that he and Hobie ran an antiques shop together. He becomes friends with Hobie and encounters the red-haired girl, Pippa, who lived with Welty and Hobie after her mother (Welty's half-sister) died of cancer.

Theo's life is disrupted when his deadbeat dad arrives with his new girlfriend and whisks him away to Las Vegas. He takes the painting with him, and in Las Vegas, makes a new friend, Boris, the cosmopolitan son of a Ukrainian émigré. The two boys, both with absentee parents, spend most of their afternoons drinking, smoking marijuana, and using other illegal drugs. Theo's father gets drunk and dies in a car crash. Theo decides to return to New York. With nowhere to stay, he heads to Hobie's, who welcomes him. Pippa, now enrolled in a school for troubled teens in Switzerland, is visiting on break.

The narrative skips ahead eight years. Theo has become a full partner in Hobart's business. He has concealed The Goldfinch because he is afraid of being accused of theft. He is engaged to a childhood friend but is still confused and obsessed with this "love" for Pippa, who is living in London with her boyfriend. Over the years, he becomes addicted to prescription medication and saves Hobie from bankruptcy by selling fake antiques.

Theo is racked by guilt and fear over the fakes and The Goldfinch. Boris reappears, now a wealthy man thanks to dubious unspecified activities. To Theo's astonishment, Boris reveals that he had stolen The Goldfinch from Theo while they were in high school; the painting has since been used as collateral by criminals and drug dealers. Boris feels guilty and has devoted himself to recovering the painting and returning it to Theo. At Theo's engagement party, Boris appears with a plan to retrieve The Goldfinch. They fly to Amsterdam to meet with the dealers who have the painting. Boris and his associates steal it back but the plan goes awry when armed henchmen confront them. In the resulting conflict, Boris is shot in the arm and Theo kills Boris's attacker while one of the dealers escapes with the painting.

Boris disappears, leaving Theo in his hotel room, where he drinks and takes drugs, afraid that police will discover him. Unable to return to New York, he feels trapped and contemplates suicide. After several days, Boris returns and reveals that he has resolved the situation by phoning the art recovery police to inform on the dealers. Not only has the painting been saved for the museum, but Boris has received a huge reward, which he shares with Theo.

After arriving in the United States, Theo travels the country, using the reward money to buy back the fake antiques from customers. In a lengthy reflection, he wonders how much of his experiences were unavoidable due to fate or his character, and contemplates The Goldfinch and "the history of people who have loved beautiful things, and looked out for them, and pulled them from the fire".