Background: Depression is a highly complex psychiatric disorder that remains a major burden on society. The present study was aimed to detect the neuroprotective effect of agomelatine or/and vitamin D3 on the progression of depression induced by chronic administration of corticosterone. Methods: Rats were classified into 4 equal groups; corticosterone-untreated group, agomelatine-treated group, vitamin D3-treated group, and (agomelatine and vitamin D3)-treated group. Results: Agomelatine or/and vitamin D3 caused significant improvement of behavioral parameters of depression, increase in serotonin, dopamine, and brain-derived neurotrophic factor (BDNF) with a significant decrease in tumor necrosis factor (TNF)-alpha and caspase-3 levels of brain tissue with a more significant effect of combination therapy over the effect of each drug alone. Conclusions: Vitamin D3 augments the antidepressant effect of agomelatine against depressive-like behavior in rats.