The Book of Unknown Americans by Cristina Henriquez, as can be inferred from the title, details the lives of several people living in the United States from their unique perspectives. Specifically, all of the speakers are Hispanic, and therefore they chronicle multiple stories and cultures in a singular novel.

Although the novel does vary in point of view, the central plot revolves around the Rivera family and their experiences transitioning into life in the United States when they move from Mexico to try to provide a better special-education setting for their daughter, Maribel, who suffers from a traumatic brain injury. The adjustment proves very difficult for them, and some of the only hope they experience is found in developing relationships with their apartment's neighbors. Maribel is even able to form a friendship and romance with a young boy in the building, Mayor Toro. It is often these neighbors who appear later in the novel to explain their own backgrounds before the novel reverts back to the Riveras' story.

As the Riveras struggle to work and to learn the language—and find some success in doing so—they are encountered with several other human challenges. One of these is through the teenage boy, Garrett Miller, who taunts both Mayor and Maribel. When Arturo Rivera goes to Garrett's home to confront him, he is shot in a horrifically tragic scene. The novel ends with Alma and Maribel Rivera returning to Mexico with the hope of Maribel's continued recovery.