In the Lake of the Woods follows the struggle of Vietnam veteran John Wade trying to deal with a recently failed campaign for the United States Senate.

After moving to Lake of the Woods County, Minnesota, John discovers one morning that his wife, Kathy, is missing.

Through flashbacks to John's childhood, college years, and war experiences, as well as testimony and evidence from affected characters, the novel provides several hypotheses for Kathy's disappearance, without resolving the question.

As a child, John was frequently abused verbally and emotionally by an alcoholic father, who was admired by other children for his public persona.

He was elected as lieutenant governor of Minnesota and later ran for the US Senate, with his campaign managed by the business-oriented Tony Carbo.

John and Kathy intentionally choose this setting for its isolation, which they seek to forget the stress and emotion of the failed election.

As they move to Lake of the Woods to relax, John and Kathy realize that their paths have drifted farther apart than initially believed.

Verlyn Klinkenborg of the New York Times wrote that the novel contains three kinds of stories: "The first is a conventional, remote third-person account of plain facts, the events that can be reconstructed without conjecture, more or less.

The second kind of story appears in several chapters called "Evidence": collections of quotations, excerpts from interviews and readings that bear on the Wade case.

The third kind of story appears in chapters called "Hypothesis"; it tries to suggest what might have happened to Kathleen Wade in the days after she disappeared.

"[1] Ellen Datlow praised the novel lavishly, saying "O'Brien continues to mine the Vietnam War and U.S. involvement in it for riches that he transmutes into art with his beautiful writing and interesting plot structure.