Lack of food is one of the most common natural stressors that animals face, yet the physiological response to food restriction in most nonmammalian species is poorly understood. Food restriction can elicit an elevation of plasma glucocorticoid hormones and changes in blood metabolites in several vertebrates, but this has not been shown in snakes, despite their remarkable ability to tolerate food shortages. The purpose of this study was to determine the physiological response to moderate food deprivation in Common Watersnakes (Nerodia sipedon). When food was withheld for 15 d, snakes lost body mass, had elevated baseline plasma corticosterone concentrations, lower hematocrit, and depressed levels of triglycerides and uric acid. Food deprivation had no effect on blood glucose or lactate. Elevation of corticosterone levels could help snakes mobilize stored energy to allow them to survive periods of restricted feeding. Depressed triglycerides likely indicate increased utilization of lipid stores. Because uric acid is the main excretory product of protein breakdown in reptiles, the decreased uric acid we observed suggests that snakes were not utilizing their stored protein. Protein stores may be conserved during short-term food deprivation, but could be utilized during more severe food shortages. These results help illuminate the physiological and behavioral mechanisms watersnakes employ to survive food shortages and serve as useful reference values for future studies looking at longer periods of food deprivation.