Nightwood is, first and foremost, the story of how the protagonist, Robin Vote, ruins the lives of nearly everyone she comes into contact with. She leaves her husband and their mentally challenged son, she cheats on her girlfriend, and she just cannot, for the life of her, seem to settle down with anyone.

Djuna Barnes, the author, wrote this book after a doomed affair with a sculptor named Thelma Wood. The angst in the story and the instability of the protagonist could arguably be representative of Barnes's own lost love, although this is not the only thematic element in play.

The story relies heavily on metaphors and images, which the reader picks up on at first glance from chapter titles such as "Night Watch" and "The Squatter," which suggest what the chapter holds. In "Night Watch," for example, the story of Nora and Robin's relationship is told, culminating with a scene at the end of the chapter in which Nora follows Robin at night, and finds her in the embrace of another woman. In "The Squatter," Nora feels that Jenny, the woman whom Robin was embracing and having an affair with, takes over other people's lives and just settles in, much like a squatter would in a house that does not belong to them.