The narrative follows the fragmented, hallucinatory experiences of William Lee, a drug addict navigating a surreal landscape of addiction and paranoia. Lee assumes various aliases as he flees from the United States to Mexico and eventually to the nightmarish, dreamlike locale known as Interzone. His objective is elusive, often obscured by the shifting reality of his surroundings and the physical toll of his chemical dependencies. The text operates as a non-linear series of vignettes, forcing the reader to piece together a reality that is constantly dissolving under the weight of the protagonist's internal and external chaos.

This work is widely recognized as a foundational text of the Beat Generation and a significant experiment in mid-century literary form. Critics often highlight its radical departure from conventional storytelling, noting how the non-linear structure mirrors the disorientation of the protagonist's addiction. While some readers find the fragmented nature and explicit content challenging to navigate, others praise the text for its uncompromising vision of societal collapse. The novel remains a subject of intense academic study regarding its influence on postmodern literature and its critique of mid-century American culture. Its status as a cultural touchstone persists despite the polarizing nature of its stylistic choices.