Oskar Schell, a nine-year-old boy, has not been happy since his dad died in the 9/11 terrorist attacks. Unbeknownst to anyone except for Oskar, on the day of the attacks, Oskar’s dad called the house five times. Oskar was home for the fifth call but couldn’t bring himself to pick up the phone. They never recovered his dad’s body and buried an empty casket at his funeral. Oskar is furious that his mom has started to spend time with a man named Ron and worries that she has begun to move on. Oskar suffers from extreme anxiety and imagines whimsical inventions in order to cope. One night, he decides to look through his dad’s closet and sees a vase hidden on the top shelf. In trying to retrieve it, Oskar drops the vase, and when it shatters, he finds an envelope labeled “Black” that contains a strange key. After doing some research, Oskar decides to visit every person with the last name Black in New York City to try and discover what the key opens.

There is also a parallel storyline about Oskar’s grandparents. The novel includes letters from Oskar’s grandpa, Thomas, to his dad, and letters that his grandma writes to him. Thomas stops speaking not long after immigrating to America out of grief for Anna, his lost love who died in the bombing of Dresden. Thomas communicates by writing one-line sentences in notebooks. He explains that Grandma, Anna’s sister whose name we never learn, encountered him in a bakery and asked him to marry her. Grandma writes her own version of their meeting, which doesn’t quite match up with Thomas’s account. According to Grandma, when she reunited with Thomas, he asked her to pose for a sculpture. She agreed and started going to his apartment daily to pose. Although he started touching her for longer and longer in order to get her into the position he wanted, the sculpture still looked like Anna. Eventually, they had sex, and Grandma proposed. Throughout their marriage, they divide up their apartment into “Nothing” places, where they can go to not exist, and “Something” places. However, the lines blur. After Grandma becomes pregnant, Thomas leaves for Dresden because he doesn’t want to keep living any longer.

Early in Oskar’s search for the key, he meets Abby Black, an epidemiologist who lives in Greenwich Village. Throughout their conversation, he hears a man yelling from the next room, but Abby ignores him. Abby claims to know nothing about the key, but Oskar notices she seems to hold something back. Nevertheless, his search continues alphabetically down his list of people named Black. He eventually meets a man only referred to as Mr. Black, who lives in the apartment right above Oskar’s. Mr. Black is 103 years old, very wise, and hard of hearing. Oskar invites him to join him in the quest for the key, but Mr. Black hasn’t left the house in the twenty-three years since his wife’s death, and he’s turned off his hearing aids. He allows Oskar to turn his hearing aids back on. From then on, Mr. Black accompanies Oskar on his travels through the city, encouraging Oskar to get over his fear of public transportation. After they meet with Ruth Black, who lives in the Empire State Building, Mr. Black tells Oskar he’s done searching for the lock. Oskar is devastated.

Thomas returns to New York after 9/11 with a desire to try and live again. Grandma at first wants him neither to stay nor leave, but she eventually allows him to stay in the guestroom. She makes him promise never to let Oskar know he’s there. After Thomas sees Oskar for the first time, he starts following him around from a distance. Mr. Black eventually confronts Thomas and tries to protect Oskar. When Thomas explains who he is, Mr. Black tells him that he should be the one going around with Oskar. Not long after, Oskar finds Thomas in Grandma’s apartment and assumes him to be Grandma’s mysterious renter. Oskar tells Thomas the story of the key and plays him the messages his dad left on the answering machine. Thomas tells Oskar if he ever needs him to toss stones at his window. Oskar later asks Thomas to help him dig up his dad’s grave. Thomas agrees, and they bury Thomas’s unsent letters to his son in the grave. Afterward, Thomas tries to leave Grandma again, but she follows him to the airport. He doesn’t want to stay or leave, so they stay there, writing.

Not long after Oskar meets Thomas, he notices that there has been a single message on his family’s answering machine for months. He listens to it and discovers that Abby Black called him because she had information about the key. He returns to her house and learns that the key belongs to her ex-husband, William. Furthermore, Oskar’s mom knew about Oskar’s key quest all along and had called Abby Black, along with many of the other Blacks, to tell them Oskar was going to be coming. Confused and frustrated, Oskar goes to William's office. William explains that the key unlocks a safety deposit box that William’s deceased father left for him. William didn’t realize the key was in the vase until after he’d sold the vase to Oskar’s dad at an estate sale. Disappointed that the key had nothing to do with his dad, Oskar goes home. He formulates a plan to dig up his dad’s grave. He looks at a series of photographs he has of a man falling from the World Trade Center. He reorders the photographs so that the man floats back up and imagines his last night with his dad playing out in reverse.