Professor St. Peter is not truly old, but he is starting to feel old. He and his wife have moved into an elegant new house, and he struggles to leave his previous study-the spartan attic room where he wrote his eight-volume life's work, a history of the Spanish in North America. Visits from his now-married daughters and their husbands leave him unexpectedly distraught. He begins to feel discomfort with his own life, home, and family.

As the professor searches for harmony, he reflects back on an earlier time when his student Tom Outland, an orphan from the Southwest, brought a unique energy and joy into his life. Though Tom was killed in World War I, the impact he had on the professor's family changed their lives in ways both good and bad, and the professor reflects on this as he revisits a notebook from Tom's discovery and exploration of an abandoned cliff dwelling in New Mexico.

One of Cather's less well-known novels, The Professor's House is considered a masterpiece by many. Themes of innocence and civilization, friendship and family, intertwine as the professor searches for an answer to his questions about what makes life worth living.