Told from the perspective of Oskar Schell, a nine year old who is constantly inventing, it is revealed immediately that his father passed away. We learn not long after that his father, Thomas, was killed in the September 11 attacks on the World Trade Center. After being let out of school early on the day of the attacks, Oskar comes home and finds 4 messages on the answering machine left by his father. While he is there, Thomas calls. Through the remainder of the novel each message, and the call made while Oskar was at home, are slowly revealed. He has hidden the messages from his mother, so he is the only one who knows what they say. The day of the attacks, and his father's death, are hence referred to as "the worst day".

Oskar lives with his mother, but his grandmother also lives just across the street. His grandfather left the family before his father was born, but we periodically read letters written to Thomas, as well as letters written to Oskar by his grandmother. One day Oskar, missing his father, goes into Thomas' old closet where he accidentally knocks over a blue vase, and finds a key inside an envelope with the name "Black" written on it. Oskar decides he has to figure out what the key opens, and so embarks on a journey to speak with every "Black" in New York until he finds the one who knows about the key. He hopes to find out exactly how his father died so that he can stop "inventing" deaths for him.

He begins to meet various characters, including one who lives just upstairs. This 103 year old man agrees to join Oskar on his journey. Meanwhile, we read a story of how the grandfather lost his voice due to the death of his lover in the bombing of Dresden. When the grandfather meets his lover's sister, they get married, but their relationship has little love. He lives upon finding out the grandmother is pregnant with Thomas. He returns to New York when he learns of his son's death, and begins to live with his wife again. Oskar does not know this, and only hears of him as "the renter"

After meeting a woman who lives on the top of the Empire State building, Oskar's 103 year old companion decides to stop travelling with him. Oskar, devastated, goes to see Grandma, but finds the renter there instead. They "talk", but Oskar does not realize who he really is. Oskar, who wants to give up on his quest to find what the lock opens, decides to dig up his father's grave with the renter's help in order to have closure. (The coffin is empty).

Out of desperation, Oskar plays a message on the phone only to learn that one of the first people he visited (8 months ago) actually knew something about the key she wouldn't reveal. The message had been on the phone the whole time. He then realizes that his mother knew about what he was doing all along. He goes to the woman who called, and she tells him her husband knows about the key. The husband tells him the key opens a safety deposit box that his deceased father had left for him. Thomas Schell had bought the vase at an estate sale before the man realized there was a key in it.

Oskar decides not to join the man in opening the safety deposit box, but he does tell the man what happened when Thomas called on the "worst day" when Oskar was at home. The phone rang, but Oskar could not pick it up. His father asked 11 times "Are you there?" but Oskar was never able to pick up the phone. After the 11th time, he is cut off. This is at 10:28, when the second building fell.

Oskar and the renter dig up the grave. The grandfather fills the coffin with all the letters he wrote, but never sent to his son. Oskar and his mother have a moment of understanding with each other, and while it is still sad, it is clear that the healing process for both of them has taken a step forward.