We tested whether white-footed mice (Peromyscus leucopus) modulate the activity of three key intestinal digestive enzymes (maltase, sucrase, and aminopeptidase-N [APN]) based on diet composition. To test the adaptive modulation hypothesis (AMH), we fed mice either of three kinds of synthetic diet, high starch (HS, 50% carbohydrate), high protein (HP, 60% protein), and high lipid (HL, 25% lipid), and determined their digestive responses. First, there was no effect of either diet itself, or time eating the diet, on body mass, or mass and length of small intestine. Second, the activity of both disaccharidases summed over the entire small intestine was highest on the HS diet, which was higher than on the HP diet by about 45% and higher than on the HL diet by 400%. This was consistent with our prediction that starch induces disaccharidase activity, and demonstrated induction of disaccharidase activities by high dietary carbohydrate in a wild mammal. Third, both summed and mass-specific activity of maltase and sucrase of HL mice were lower than those of HP mice, even though their diets had the same content of starch, which suggests that lipid in the HL diet inhibited disaccharidase activity. Finally, the summed activity of APN was highest on the HP diet, which was higher than on the HS diet or HL diet by ~100%, consistent with our prediction that high protein content induces peptidase activity. Taken together, our results support the AMH, though they also illustrate that high lipid content in the diet can confound some predicted patterns. Flexibility of digestive enzyme activity is likely important in allowing white-footed mice to cope with fluctuations in the environmental availability of different food types.