Given the robust influence of diet and exercise on brain plasticity and disease, we conducted studies to determine their effects on molecular systems important for control of brain homeostasis. Studies were centered on a battery of proteins implicated in metabolic homeostasis that have the potential to modulate brain plasticity and cognitive function, in rat hypothalamus and hippocampus. Adult male rats were exposed to a docosahexaenoic acid (DHA) enriched diet (1.25% DHA) with or without voluntary exercise for 14 days. Here we report that the DHA diet and exercise influence protein levels of molecular systems important for the control of energy metabolism (primarily phospho-AMPK, silent information regulator type 1), food intake (primarily leptin and ghrelin receptors), stress (primarily glucocorticoid receptors), and 11beta-hydroxysteroid dehydrogenase 1 (11βHSD1). Exercise or DHA dietary supplementation had differential effects on several of these class proteins, and the concurrent application of both altered the pattern of response elicited by the single applications of diet or exercise. For example, exercise elevated levels of glucocorticoids receptors in the hypothalamus and the DHA diet had opposite effects, while the concurrent application of diet and exercise suppressed the single effects of diet or exercise. In most of the cases, the hypothalamus and the hippocampus had a distinctive pattern of response to the diet or exercise. The results harmonize with the concept that exercise and dietary DHA exert specific actions on the hypothalamus and hippocampus, with implications for the regulations of brain plasticity and cognitive function.