To understand the importance of plasticity of central processing organs (i.e., stomach and intestinal organs) to animals in the wild, field studies of changes in organs and their relationships with variable environmental conditions and energy demands are needed. We determined relationships among diet quality, indicators of energy demand, sizes of central processing organs, and rate of nutrient uptake in free-living white-footed mice (Peromyscus leucopus) in western Kentucky. Moderate winters and dry summers characterized the study site. In contrast to studies conducted in more extreme environments, we found limited differences in the sizes and function of central processing organs among seasons. Masses, but not lengths of intestinal organs or the rate of glucose uptake, differed among seasons. Heart and spleen masses, but not masses of the lungs, kidneys, or liver, also differed among seasons. Differences in the amount of food ingested and percentage of protein in the diet were likely contributors to seasonal differences in intestinal organ masses. Lactation was associated with heavier masses of all central processing organs and increased rate of glucose uptake, but not with heavier masses of vital organs. Greater size and function of intestinal organs during lactation was attributed primarily to high energy demand and secondarily to diet. We postulated that large changes in size and function of central processing organs in free-living mammals occur during intense, but not moderate, changes in energy demand and diet composition and are dependent on the type of energy demand incurred.