Chronic stress exerts profound effects on mental health, contributing to disorders such as depression, anxiety, and cognitive impairment. This study examines the potential of psilocybin to alleviate behavioral despair and cognitive deficits in a rodent model of chronic stress, focusing on the interplay between the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Endocannabinoid System (ECS). Twenty-two male Wistar rats were divided into control and stress groups. Animals within the stress group were exposed to predator odor and chronic social instability to induce chronic stress, and were either sham treated, or given psilocybin. Behavioral assessments were conducted using the Open Field Test, Sucrose Preference Test, Novel Object Recognition, Elevated Plus Maze, and Forced Swimming Test to evaluate locomotion, anhedonia, memory, anxiety, and behavioral despair, respectively. Blood and brain samples were analyzed for biochemical markers. Results indicated that psilocybin significantly reduced stress-induced behavioral despair and cognitive impairments, likely through ECS-mediated downregulation of the HPA axis. These findings suggest that early intervention with psilocybin has sustained beneficial effects on stress-related behavioral and cognitive disturbances, underscoring its potential as a novel therapeutic approach for stress-related mental health disorders.