Set at a bucolic midwestern college, White Noise follows a year in the life of Jack Gladney, a proffesor who has made his name by pioneering the field of Hitler Studies (though he doesn't speak German). He has been married five times to four women and has a brood of children and step-children with his current wife, Babette. In its first half called "Waves and Radiation", White Noise is a chronicle of absurdist family life combined with academic satire.

In the second half, a chemical spill from a railcar releases an "Airborne Toxic Event" over Jack's home region, prompting an evacuation. Frightened by his exposure to the toxin, Gladney is forced to confront his mortality. Ironically, Gladney also realizes that his wife has been cheating on him in order to gain access to a drug called Dylar, an experimental new treatment for the fear of death. Soon the novel becomes a meditation on modern society's fear of death and its obsession with chemical cures as Gladney seeks to obtain his own black market supply of Dylar.