Animals in nature use synergistic behavioral and physiological responses to cope with variation in resource availability. We used a combination of traditional tools (i.e., radiotelemetry, body-condition measurements, plasma osmometry, and direct observation) and contemporary techniques (i.e., implanted temperature loggers and portable ultrasonography) to identify seasonal patterns of body condition, hydration state, and surface activity of 16 free-living Gila Monsters during two active seasons. Despite seasonal drought each year, Gila Monster snout–vent length increased during the study; yet body mass, tail volume, and hydration state decreased. Generally, surface activity was associated with rainy periods, and males were significantly more active than females but only during the reproductive season. Our results indicate that Gila Monsters combine flexible behavioral patterns (i.e., the timing and duration of surface activity), resource storage and economical use, and tolerance of substantial physiological disturbance to endure seasonal resource limitations at a site in the Arizona-Upland subdivision of the Sonoran Desert.