Walnut polyphenols (WP) is an important bioactive substance in defatted walnut and has important development and application value. In order to evaluate the antidepressant effect of WP on corticosterone-induced damage of rat pheochromocytoma (PC12) cells by cell viability, cell apoptosis, leakage of extracellular lactate dehydrogenase, and intracellular calcium level, and investigated its mechanisms by western blotting. The results showed that WP (75,150μg/mL) pretreatment could protect cell by significantly reversing the cell viability decrease, cell apoptosis, LDH release increase, and overload of intracellular calcium in PC12 cells treated with corticosterone. In addition, WP significantly increased the activity of cAMP-dependent protein kinase A (PKA), reduced the level of Ser133 phosphorylation of cAMP response element binding protein (CREB) and the expression of downstream target protein brain-derived neurotrophic factor (BDNF), which were decreased by corticosterone treatment. Furthermore, pretreatment with PKA inhibitor H89 abolished the protective effects of WP on corticosterone induced PC12 cells, indicating that up-regulation of PKA/CREB/BDNF neurotrophic signaling pathway was required for WP neuroprotective effects against corticosterone. These results suggested that WP might have potential antidepressant activity and be an important material basis in the antidepressant effect of walnut diet. The cytoprotective effect of WP on PC12 cells was related to the up-regulation of PKA/CREB/BDNF neurotrophic signaling pathway. The research results aimed to explore the potential antidepressant activity and mechanism of walnut polyphenols, and provided theoretical reference for the high-value utilization of walnut meal.