Oskar Schell is a nine-year-old boy whose father, Thomas Schell, died in the terrorist attacks on the World Trade Center on September 11, 2001. The novel begins after the tragedy, with Oskar narrating. Since his father’s death, Oskar struggles with insomnia, panic attacks, and depression. He often describes the feeling of depression as wearing heavy boots, and deals with this by giving himself bruises.
While looking through his father's closet, Oskar finds a key in a small envelope inside a vase he smashed; on the outside of the envelope the word "Black" is written in the top left corner. Curious, Oskar sets out on a mission to contact every person in New York City with the last name Black, in alphabetical order, in the hope of finding the lock that belongs to the key his father left behind. One of the first people Oskar meets in his search for the key's origin is a 48-year-old woman named Abby Black. Oskar and Abby become friends instantly, but she has no information on the key. Oskar continues to search the city, towards the end of his journey Oskar meets an old man he calls "the renter" because until the point of meeting, Oskar had only heard of the old man's existence from his Grandmother who referred to him as the new tenant in her apartment. (We learn towards the end of the book that "The renter" is actually Oskar's grandfather.)
The book spans many months of Oskar's journey, some of which he was accompanied by his elderly neighbour, Mr. A. Black. Eight months after Oskar initially met Abby, he finds a message from her on the answering machine. Oskar had not touched that phone since his father died because his father's last words had been on an identical answering machine which Oskar had kept hidden from his mother. Oskar finds out that Abby called him directly after his visit, saying she wasn't completely honest with him and might be able to help. Oskar returns to Abby's apartment after listening to this message, and Abby directs him to her ex-husband, William Black.
When Oskar talks to William Black, he learns that the key once belonged to William's father. In his will, William's father left William a key to a safe-deposit box, but William had already sold the vase at the estate sale to Thomas Schell. Then, Oskar tells William something that he "never told anyone" – the story of the last answering machine message Oskar received from his father, during the attack of 9/11. Oskar then gives William Black the key. Disappointed that the key does not belong to him, Oskar goes home angry and sad, not interested in the contents of the box. After Oskar destroys everything that had to do with the search for the lost key, Oskar discovered that his mother knew about his activities the entire time and was contacting everyone with the name Black in New York City. After the first few visits she called every Black that he would meet and informed them that Oskar was going to visit and why. In response, the people Oskar met knew ahead of time why he was coming and usually treated him in a friendly manner.
The novel has a parallel narrative that eventually converges with the main story. This narrative is portrayed through a series of letters written by Oskar's grandfather to Oskar's father Thomas, and by Oskar's grandmother to Oskar himself. The letters written by Oskar’s grandfather explain his past in World War II, his first love, and his marriage to Oskar’s grandmother. The letters written by Oskar’s grandmother explain her past in meeting Oskar’s grandfather, the trouble in their relationship, and how important Oskar is to her.