Activation of the hypothalamic-pituitary-adrenal (HPA) axis regulates immune and inflammatory responses through modulation of cytokines, white blood cells (WBCs), and oxidative stress. However, little is known about the impact of HPA axis activation during extreme physiological conditions in marine mammals. We challenged 18 post-weaning (simultaneously fasting and developing) northern elephant seal pups with daily intra-muscular injections of adrenocorticotropin (ACTH), a glucocorticoid receptor (GR) antagonist (RU486), or a combination (ACTH+RU486) for four days. Animals were blood sampled at baseline, 2 hours (2h), and 4 days (4d) after the beginning of the treatment. ACTH and ACTH+RU486 elevated aldosterone and cortisol at 2h, with the effect diminishing at 4d. RU486 alone induced a compensatory increase in aldosterone, but not cortisol, at 4d. ACTH decreased neutrophils (N) at 2h while decreasing lymphocytes (L) and increasing N:L ratio at 4d. These effects were abolished by RU486. Despite alterations in WBCs, there was no effect of ACTH on TGF-b or IL6; however, both cytokines decreased across the fast (4d). Similarly, ACTH did not impact protein oxidation, lipid peroxidation, or antioxidant enzyme activities, but lipid peroxidation and catalase decreased while glutathione peroxidase increased with fasting progression. These data show that HPA axis activation has differential acute (2h) and chronic (4d) modulatory effects on WBCs and that the chronic effect is mediated, at least in part, by GR signaling. These results also underscore the robustness and tolerance of these elephant seals to repeated HPA activation.