Abstract Background: Chronic unpredictable stress could alter the synaptic regulation, morphological changes of neurons, and adult neurogenesis. The severity of these changes varies in proportional to the duration and intensity of stress. Aim of Study: This study aimed to investigate the delete-rious effect of the chronic unpredictable stress on the brain's cognitive function, focusing on the expected modulations on the adult neurogenesis in the hippocampus. Material and Methods: Twenty-four adult male albino rats were divided equally into two groups. Control group (stayed safe with free access to food and water), and chronic unpredictable stress group exposed to different stressors at different times for 25 days. Barnes Maze assessed cognitive performance (spatial learning and memory performance). We evaluated serum corticosterone serum level, oxidative stress, and the antioxidant capacity in the hippocampus. The hippoc-ampal neural cell proliferation was assessed using basic fibroblast growth factor2 (bFGF2), histological and immuno-histochemical examinations using an ionized calcium-binding adaptor (Iba-1) for microglial activity and doublecortin (DCX) as an indicator of hippocampal adult neurogenesis. Results: The chronic unpredictable stress group showed a significant decline (p<0.05) in cognitive performance. Also, it exacerbated the oxidative stress in the hippocampus in parallel with high corticosterone serum levels. Increased expression of bFGF2 and DCX in chronic unpredictable stress revealed the tendency of the neural stem cells towards proliferation. Conclusion: The deleterious effect of the unpredictable chronic stress on the hippocampus is partly due to the over activation of the neural stem cells and microglia, leading to an incomplete process of neurogenesis proved by the deteri-orated behavioral tests.