Depression is a highly prevalent and disabling psychiatric disease that often requires long-term treatment. This study was planned to investigate the antidepressant activity of DHEA in the experimental model. This study was conducted on 40 adult male albino rats assigned into 4 groups; Gp. (1) control group, Gp. (2) reserpinized group, Gp.(3) reserpinized group treated with low dose of DHEA and Gp.(4) reserpinized group treated with high dose of DHEA. Brain neurotransmitters, serum ACTH and corticosterone, brain proinflammatory cytokines, brain derived neutrophic factor and brain antiapoptic mediator as well as the histological examination of the brain tissue sections were carried out. In comparison with the control group, the reserpinized group recorded significant decrease in serotonin, dopamine, BDNF and Bcl-2, significant increase in ACTH, corticosterone were detected in the reserpinized group. Histological examination of brain tissue sections of rats in the reserpinized group showed neuronal damage and shrinkage. On the other hand, treatment of the reserpinized groups with either low or high dose of DHEA resulted in remarkable improvement in the biochemical parameters associated with restoration in the structure organization of the brain in a dose dependant manner. The present work provides a clear evidence for the antidepressant potential of DHEA. This was evidenced by activation of serotoninergic and dopaminergic system, reduced levels of ACTH and corticosterone, inhibition of proinflammatory cytokines, promotion of neurotrophic factor and improvement the morphological structure of the brain tissue sections.