AIM: This study was aimed to investigate the effects of sodium benzoate in chronic unpredictable mild stress (CUMS)-induced depression model in rats. MATERIAL AND METHOD: Male rats were exposed to CUMS stress for 6 weeks which includes with multiple unpredictable stressors to induce depression related symptoms and the treatment with sodium benzoate was started at the 4th week of stress protocol (i.e. on the 22nd day) for 21 days during stress protocol . RESULTS: CUMS significantly increased the immobility period in the forced swimming test and decrease sucrose consumption in the sucrose preference test in rats. In the prefrontal cortex region (PFC) of the brain, a significant decline in the Brain-derived neurotrophic factor (BDNF) levels and Protein kinase A (PKA) was observed in rats. However, sodium benzoate (400 and 800 mg/kg i.p.) significantly restored sucrose preference behavior as well as reduced immobility in CUMS-subjected rats in a dose-dependent manner, suggesting the antidepressant potential of sodium benzoate. Also, sodium benzoate treatment significantly increased BDNF levels and PKA activity in the PFC region of the stress subjected rat brain. Moreover, co-administration of H-89, PKA inhibitor (1 and 5 mg/kg) along with sodium benzoate (800 mg/kg) in CUMS subjected rats notably attenuated antidepressant effects of sodium benzoate. H-89 also abolished sodium benzoate-mediated increase in BDNF levels and PKA activity in stress-subjected rats. CONCLUSION: Sodium benzoate mediated antidepressant actions may be due to a decrease in the d-amino oxidase activity, an increase in BDNF, and PKA levels in PFC region of the brain. Sodium benzoate-mediated modulation of BDNF/PKA signaling may contribute to attenuating depressive-symptoms in unpredictable stress-subjected rats.