Turtles All the Way Down tells the story of Aza Holmes, an Indiana teenager living with a mental illness. Aza deals with intrusive thoughts and compulsive behavior, particularly relating to bacteria. She regularly researches C. diff, a type of bacteria that can cause a deadly infection. She also focuses on her middle finger, which has a callus that she often opens up to make bleed. As Aza thinks about the bacteria around her in the school cafeteria, Daisy, her best friend, tries to get Aza’s attention to ask her about Davis Pickett. Aza knew Davis from camp and knows that he is from a wealthy family. Daisy tells Aza that there is a reward for information about Russell Pickett, Davis’s father, who has disappeared. After school, Aza and Daisy change their plans of taking Daisy to work so they can go to the Pickett’s property to investigate.
Aza knows about a camera in the woods at the edge of the Pickett’s property. On the camera she finds a photo of Russell from the night of his disappearance. While Aza and Daisy look at photos, Lyle, the Pickett’s security guard, finds them. He takes them to the Pickett’s house, where Davis sees Aza and informs Lyle that he knows her. Daisy tells Davis that Aza has a crush on him, and Davis tells Aza that he often thinks about her. They exchange numbers with the hope of staying in touch, but Davis expresses his concern she is only after the reward money. He wishes she had come by because of him and not because of the money.
Although Aza tells Daisy that she is not looking for a romantic relationship, she continues to think about Davis. Meanwhile, Daisy keeps encouraging Aza to find out more information about Russell’s disappearance so they can get the reward. Aza worries that investigating will affect Davis, but she continues to search anyway. They find out that Russell left his fortune to research on tuatara (lizard-like reptiles known for their long lives) and nothing for his sons, and that he has legal troubles related to unethical business practices.
Aza and Davis eventually text each other and they go on a double date with Daisy and her boyfriend, Mychal. After dinner, the four go to the Pickett’s home and Aza and Davis go outside. They share vulnerable details about their lives while they look at the sky. Aza shares some of her intrusive thoughts and tells Davis that she does not feel in control of her life. He tells her about the grief of losing his mom and his dad not being present. Davis is afraid that Aza may still be after the reward money and may not actually like him, so he gives her $100,000 as a reward for not sharing any information about Russell’s disappearance.
Aza tell Daisy that Davis gave them $100,000 to not share any information with the police. They split the money and Daisy begins making large purchases to celebrate, such as buying a car and a laptop. Aza disapproves of Daisy’s spending and continues to meet with Davis. Aza likes being with Davis and eventually decides to kiss him. As they kiss, intrusive thoughts about bacteria that they may exchange while kissing distract Aza. She excuses herself and compulsively rinses her mouth to try to make herself clean. She tells her psychiatrist, Dr. Singh, about this new panic the next day. Dr. Singh points out that even good change is stressful and she encourages Aza to take her medicine every day despite Aza’s fear that it will take away her control over who she is.
Aza struggles to adjust to the changes in her life. She worries about Davis and his brother, Noah, not having a father. So, at Noah’s request, she continues to search for information. Noah sends Aza notes from Russell’s phone, which was left at the house, to help Aza with her research. Aza’s fear of bacteria from kissing Davis continues and she feels compelled to drink hand sanitizer to kill the new bacteria. Aza’s relationship with Daisy also suffers because Daisy is afraid she will lose the money if Aza finds out more information. Aza also feel hurt after reading Daisy’s fanfiction, which includes a character that has similar compulsions to Aza and is described as stupid and easy to hate.
Aza eventually confronts Daisy about her depiction of the compulsive character in her stories as Aza drives her to work. Tired from drinking hand sanitizer and distracted by yelling at Daisy, Aza causes a car accident. Aza is hospitalized after the accident for a lacerated liver, which makes her even more anxious because of her fear of bacteria. In the hospital, Aza’s thoughts spiral. She repeatedly apologizes to Daisy and obsesses about the bacteria around her. She eventually gets out of bed to drink hand sanitizer to kill the bad bacteria, which alarms her mom and causes more damage to her liver. Aza’s mom and Dr. Singh are increasingly attentive to Aza and Dr. Singh adjusts Aza’s medication. She assures Aza that her thoughts are not her and that there is hope.
Aza reconciles with Daisy when she returns to school after her hospitalization, but Aza and Davis breakup. Aza explains she has trouble being close to him in person and Davis tells her that he cannot be close to her over the phone. Aza attends an art show with Daisy and Mychal. While there, she realizes the meaning of one of the notes on Russell’s phone. Aza talks to Davis for the first time since breaking up to tell him that she thinks she knows Russell’s location but he is probably dead. Davis and Noah decide to report the location to the police and they find Russell’s body. Davis sends Aza a gift, but they do not continue talking. Aza reflects on the sky and realizes, at this point, she can imagine a future with possibilities, not the hopelessness she felt before about never being close to people. She acknowledges that she is not simply controlled by outside forces in her life.