Background: Melatonin has anti-inflammatory, immunomodulatory and anti-apoptotic functions. Hippocampus and dentate gyrus are highly affected by changes in adrenal hormones. Materials and Methods: eighteen albino male rats were divided into three groups. Control group: six rats' adrenal glands were exposed without manipulation. Adrenalectomized group (AD): six rats were adrenalectomized surgically. Adrenalectomized with hormone replacement plus melatonin (AD+TTT+M): six rats were adrenalectomized and received Fludrocortisone plus Prednisone as hormone replacement and melatonin. All drugs were given orally from first day after adrenalectomy till 4 weeks. After 4 weeks rats were anaesthetized to be sacrificed then their brains were dissected. One hippocampus was homogenized for malondialdehyde quantitative analysis. Other hippocampus was used for histopathology. Results: The cresyl-stained sections of AD group showed disruption and reduction in thickness of CA1, CA3 and dorsal blade of DG, but AD+TTT+M group showed nearly normal thickness with preserved architecture of same regions. Higher magnification of CA1, CA3 and dorsal blade of DG of AD group in synaptophysin stain showed negative immune reaction but AD+TTT+M group showed synaptophysin positive granules across all layers. MDA levels were elevated in AD group, but they were back to normal levels in AD+TTT+M group. Brain weight was reduced in AD group, but it was nearly normal in AD+TTT+M group. Area percentage of Synaptophysin was reduced in all layers in AD group but elevated in AD+TTT+M group. Conclusion: adrenal hormones are important for survival of hippocampus neurons and melatonin administration in primary adrenal insufficiency to hormonal supplement may add a neuroprotective effect.