Accumulating evidence has confirmed the health benefits of walnut diets in maintaining brain function with age. Recent studies have indicated that walnut polyphenols (WP) and their active metabolites urolithins may play an important role in the health benefits of walnut diets. In the present study, we evaluated the protective effect of WP and urolithin A (UroA) on H2O2-induced damage in human neuroblastoma (SH-SY5Y) cells, and investigated its mechanisms in the cAMP-response element binding protein (CREB)-mediated signaling pathway, which is tightly involved in neurodegenerative and neurological diseases. The results demonstrated that both WP (50 and 100 μg mL-1) and UroA (5 and 10 μM) treatment significantly reversed the decrease of cell viability, the leakage of extracellular lactate dehydrogenase (LDH), the overload of intracellular calcium and cell apoptosis induced by H2O2 treatment. Moreover, WP and UroA treatment also relieved H2O2-induced oxidative stress including overproduction of intracellular reactive oxygen species (ROS) and reduced activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, western blot analysis showed that WP and UroA treatment significantly increased the activity of cAMP-dependent protein kinase A (PKA) and the expression of pCREB (Ser133) and its downstream molecule brain-derived neurotrophic factor (BDNF), which were decreased by H2O2 treatment. Furthermore, pretreatment with the PKA inhibitor H89 abolished the protective effects of WP and UroA, indicating that up-regulation of the PKA/CREB/BDNF neurotrophic signaling pathway is required for their neuroprotective effects against oxidative stress. The current work provides new perspectives for understanding the beneficial effects of WP and UroA on brain function, which warrants further investigation.