Beneficial effects of St. John's wort (Hypericum perforatum) in the treatment of stress-evoked memory impairment were recently described. In this study, we tested a hypothesis that St. John's wort alleviates stress- and corticosterone-related memory impairments by restoring levels of synaptic plasticity proteins: neuromoduline (GAP-43) and synaptophysin (SYP) in hippocampus and prefrontal cortex. Stressed and corticosterone-treated rats displayed a decline in the acquisition of spatial working memory (p < 0.001) in the Barnes maze (BM). Chronic administration of H. perforatum (350 mg kg−1 for 21 days), potently and significantly improved processing of spatial information in the stressed and corticosterone-injected rats (p < 0.001). Also, St Johns' wort statistically significantly (p < 0.05) increased levels of GAP-43 and SYP, respectively in the hippocampi and prefrontal cortex as measured by western immunoblotting. We found that H. perforatum prevented the deleterious effects of both chronic restraint stress and prolonged corticosterone administration on working memory measured in the BM test. The herb significantly (p < 0.01) improved hippocampus-dependent spatial working memory in comparison with control and alleviated some other negative effects of stress on cognitive functions. These findings increase our understanding of the reaction of the hippocampus and prefrontal cortex to stressful assaults and provide new insight into the possible actions of H. perforatum in the treatment of patients with impaired adaptation to environmental stressors and simultaneously suffering from cognitive impairment.