The story takes place in Indianapolis, Indiana, where sixteen year-old Hazel Grace Lancaster reluctantly attends a cancer patients' support group at her mother’s behest. Because of her cancer, she uses a portable oxygen tank to breathe adequately. In one of the meetings she catches the eye of a teenage boy, and through the course of the meeting she learns the boy’s name is Augustus Waters. He's there to support their mutual friend, Isaac. Isaac had a tumor in one eye that he had removed, and now he has to have his other eye taken out as well. After the meeting ends, Augustus approaches Hazel and tells her she looks like Natalie Portman in V for Vendetta. He invites Hazel to his house to watch the movie, and while hanging out, the two discuss their experiences with cancer. Hazel reveals she has thyroid cancer that has spread to her lungs. Augustus had osteosarcoma, but he is now cancer free after having his leg amputated. Before Augustus takes Hazel home, they agree to read each other’s favorite novels. Augustus gives Hazel The Price of Dawn, and Hazel recommends An Imperial Affliction.

Hazel explains the magnificence of An Imperial Affliction: It is a novel about a girl named Anna who has cancer, and it's the only account she's read of living with cancer that matches her experience. She describes how the novel maddeningly ends midsentence, denying the reader closure about the fate of the novel’s characters. She speculates about the novel’s mysterious author, Peter Van Houten, who fled to Amsterdam after the novel was published and hasn’t been heard from since.

A week after Hazel and Augustus discuss the literary meaning of An Imperial Affliction, Augustus miraculously reveals he tracked down Van Houten's assistant, Lidewij, and through her he's managed to start an email correspondence with the reclusive author. He shares Van Houten's letter with Hazel, and she devises a list of questions to send Van Houten, hoping to clear up the novel’s ambiguous conclusion. Hazel is most concerned with the fate of Anna’s mother. She figures that if Anna’s mother survives her daughter’s death, then her own parents will be all right after Hazel dies. Van Houten eventually replies, saying he could only answer Hazel’s questions in person. He invites her to stop by if she is ever in Amsterdam.

Shortly after Augustus invites Hazel on a picnic. It turns out he's planned an elaborate Dutch-themed picnic where he reveals that a charitable foundation that grants the wishes of kids with cancer has agreed to grant his: he's taking the two of them to Amsterdam to meet Van Houten. She is thrilled, but when he touches her face she feels hesitant for some reason. Over time she realizes that she likes him a lot, but she knows she'll hurt him when she dies. She compares herself to a grenade.

In the midst of her struggle over what to do about Augustus, Hazel suffers a serious episode in which her lungs fill with fluid and she goes to the ICU. When she is released after a period of days, she learns that Augustus never left the hospital’s waiting room. He delivers Hazel another letter from Van Houten, this one more personal and more cryptic than the last. After reading the letter, Hazel is more determined than ever to go to Amsterdam. There is a problem though: Her parents and her team of doctors don’t think Hazel is strong enough to travel. The situation seems hopeless until one of the physicians most familiar with her case, Dr. Maria, convinces Hazel’s parents that Hazel must travel because she needs to live her life.

The plans are made for Augustus, Hazel, and Hazel's mother to go to Amsterdam, but when Hazel and Augustus meet Van Houten they find that, instead of a prolific genius, he is a mean-spirited drunk who claims he cannot answer any of Hazel’s questions. The two leave Van Houten’s in utter disappointment, and, accompanied by Lidewij, who feels horrified by Van Houten's behavior, they tour Anne Frank’s house. At the end of the tour,