Readers are oriented to the flu-ravaged, post-apocalyptic world of Hole in the Sky through the eyes of the protagonist, Ceej Kane. Ceej is a teenage boy who lives with his uncle, known throughout the novel as Uncle, and his sister, Harryette.

These three, who live near the Grand Canyon, are among only 38 million survivors worldwide following an outbreak of a deadly flu virus. Small isolated communities have formed as survivors carve out a new way of life, where they are suspicious of outsiders, wary of traveling far from home, and desperate to avoid contracting the virus that continues to linger. However, Ceej is forced to confront his suspicions of outsiders, travel away from his familiar home, and risk infection when Uncle and Harryette go missing.

In his journey, his best friend, Tim, joins him as they encounter others who might help them find Harryette and Uncle. These other characters they meet embody the best and worst of this new, post-flu existence. They encounter the Kinka, a gang of crazed flu carriers who seek to infect others in order to grow their gang, showcasing the dangers of this new world. Tim and Ceej also meet Bella, a Hopi girl who tries to show them a new way of existing in this disease-ridden world.