Reported sightings of a hellish hound and the discovery of newly dead desiccated corpses bring Sam and Dean Winchester to Brennan, Ohio. But when they catch the monster canine it turns out to be "Frankenmutt"; a reanimated patchwork of pieces from separate dogs.

Soon the brothers are on a trail that leads from mad scientists and biotechnology to a centuries-old alchemists, walking corpses, and an ancient and malevolent power.