The hypothalamic-pituitary-adrenal (HPA) axis controls the release of glucocorticoids, which regulate immune and inflammatory function by modulating cytokines, white blood cells and oxidative stress via glucocorticoid receptor (GR) signaling. Although the response to HPA activation is well characterized in many species, little is known about the impacts of HPA activation during extreme physiological conditions. Hence, we challenged 18 simultaneously fasting and developing elephant seal pups with daily intramuscular injections of adrenocorticotropin (ACTH), a GR antagonist (RU486), or a combination of the two (ACTH+RU486) for 4days. We collected blood at baseline, 2 h and 4days after the beginning of treatment. ACTH and ACTH+RU486 elevated serum aldosterone and cortisol at 2 h, with effects diminishing at 4days. RU486 alone induced a compensatory increase in aldosterone, but not cortisol, at 4 days. ACTH decreased neutrophils at 2 h, while decreasing lymphocytes and increasing the neutrophil:lymphocyte ratio at 4days. These effects were abolished by RU486. Despite alterations in white blood cells, there was no effect of ACTH or RU486 on transforming growth factor-β or interleukin-6 levels; however, both cytokines decreased with the 4day fasting progression. Similarly, ACTH did not impact protein oxidation, lipid peroxidation or antioxidant enzymes, but plasma isoprostanes and catalase activity decreased while glutathione peroxidase increased with fasting progression. These data demonstrate differential acute (2 h) and chronic (4 days) modulatory effects of HPA activation on white blood cells and that the chronic effect is mediated, at least in part, by GR. These results also underscore elephant seals' extraordinary resistance to oxidative stress derived from repeated HPA activation.