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Ample evidence has pointed to a close link between oxidative stress, mitochondrial dysfunction, and depression. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of cellular redox homeostasis and affects mitochondrial function. Nrf2 holds promise for depression prevention and treatment. This study aimed to investigate the potential prophylactic antidepressant effect of cilostazol and the contribution of the Nrf2 pathway toward the putative neuroprotection. The behavioral and neurochemical effects of concomitant treatment of oral cilostazol at doses of 7.5, 15, and 30 mg/kg/day in Wistar rats exposed to chronic restraint stress (CRS) for 4 weeks were assayed. Cilostazol prevented CRS-induced depressive-like behavior shown in sucrose-preference, forced-swimming, and open-field tests, and hypothalamus–pituitary–adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Cilostazol prevented CRS-induced increase in hippocampal lipid peroxidation and 8-hydroxy-2′-deoxyguanosine, and a decrease in antioxidant activities (glutathione level, superoxide dismutase, and catalase). Western blot and PCR showed that cilostazol favorably modulated the Nrf2 protein and heme oxygenase-1 and NAD(P)H: quinoneoxidoreductase-1 gene expression in the hippocampus of CRS rats. Cilostazol also prevented the decrease in the hippocampal activities of mitochondrial respiratory enzyme complexes I–IV. These behavioral and biochemical findings indicated the potential prophylactic antidepressant effect and mechanism of cilostazol by preventing oxidative stress by activation of redox defense mechanisms mediated through the Nrf2 pathway and restoring mitochondrial dysfunction.