Greg Gaines is a senior at Benson High School in Pittsburgh, Pennsylvania. A social loner, he navigates high school life by gaining everyone's acquaintance but staying clear of any particular clique. His only real friend is Earl Jackson, a fellow student from a poor and broken family. Greg and Earl have been friends since childhood, but Greg will only (cautiously) claim they are coworkers. The two spend most of their time making films together. Greg and Earl keep their filming ventures a secret from their peers, fearing ridicule for their mediocre projects.
One day, Greg's mother tells him that his childhood friend, Rachel Kushner, is diagnosed with acute myelogenous leukemia. Greg's mother wants him to rekindle their friendship and make her feel better. Although Greg had only befriended Rachel to get closer to her more attractive friend, Leah Katzenberg, he realized he could not argue with his mother and called her.
One day at school, Greg gets a text from Rachel saying that she will be starting chemotherapy the next day. Although he and Earl are accidentally on drugs at that moment, they make it to Rachel's, where Greg introduces her to Earl. The three go out for ice cream, and Earl invites Rachel to watch some of their films. Greg is furious, but does not stop him.
At school, Greg begins to fall back on his studies and soon comes close to failing all his subjects. His parents pressure him to apply to a college seriously, but Greg is unsure which one to choose. He discusses it with Rachel, who tells him he should apply to a film school. Meanwhile, word gets around Benson High that Greg and Rachel have become close. Madison Hartner, Greg's long-time crush, comes to hear of his films from Rachel and persuades him to make a movie for Rachel. Greg and Earl come up with different ideas (including documentary footage, confessionals, and puppetry), and the result, entitled Rachel the Film, is a mashup of everything they try out. To Greg's horror, the film is shown to the entire school during an assembly. Upset by this, Greg stops going to school altogether and scratches all the DVDs of his movies.
A few days after the screening, Rachel dies. Greg goes to Earl to talk about it and discovers that he destroyed his copies of their movies. He is done with film-making for good. Greg tells him he will apply to film school instead of college. Earl is opposed to this, saying that Rachel's death shouldn't affect his plans.
In the epilogue, Greg reveals that he wrote the book to explain to his prospective college, the University of Pittsburgh, why he fell back on schoolwork during his last school year. After talking with Earl, he decided to retire from film-making, but after writing down his experience, he decided he shouldn't. Greg realizes he is always unhappy because he is trying to be someone he isn't, but he is content when he is just himself. He decides to apply to film school within the next six months. The book ends with him wondering if he should put Rachel in his next film.
