House of Leaves begins with a first-person narrative by Johnny Truant, a Los Angeles tattoo parlor employee and professed unreliable narrator. 

Truant is searching for a new apartment when his friend Lude tells him about the apartment of the recently deceased Zampanò, a blind, elderly man who lived in Lude's apartment building.

In Zampanò's apartment, Truant discovers a manuscript written by Zampanò that turns out to be an academic study of a documentary film called The Navidson Record directed by an acclaimed photojournalist named Will Navidson, though Truant says he can find no evidence that the film or its subjects ever existed.

The rest of the novel incorporates several narratives, including Zampanò's report on the (possibly fictional) film; Truant's autobiographical interjections; a small transcript of part of the film from Navidson's brother, Tom; a small transcript of interviews of many people regarding The Navidson Record by Navidson's partner, Karen; and occasional brief notes by unidentified editors, all woven together by a mass of footnotes. 

There is also another narrator, Truant's mother, whose voice is presented through a self-contained set of letters titled The Whalestoe Letters.

 Each narrator's text is printed in a distinct font, making it easier for the reader to follow the occasionally challenging format of the novel (Truant in Courier New in the footnotes, and the main narrative in Times New Roman in the American version, the unnamed editors are in Bookman, and the letters from Johnny's mother are in Dante).