Abstract: Background and Objectives: Anacardium occidentale L. (Anacardiaceae) has several therapeutic application in folk medicine in curing or managing a wide range of diseases. The present study was undertaken to investigate the antidepressant-like effects of Anacardium occidentale L. leaves in the mouse Forced Swim Test (FST) and Tail Suspension Tests (TST). Methodology: Acute toxicity and neurotoxicity studies were performed. In acute study, ethanolic extract at a dose of 200 and 400 mg kg-1 were administered in single dose one hour prior to the test. In the chronic study, extracts were administered once daily for a period of 14 days. Imipramine (10 mg kg 1) and fluoxetine (10 mg kg 1) were used as standard antidepressant agents throughout the study. The extract did not show any type of toxicity. Results: The results showed that the ethanolic extract decreased immobility periods significantly in a dose dependent manner in both Tail Suspension Test (TST) and Forced Swim Test (FST). The observed results were also comparable with known standard drugs. The flavonoids apigenin and quercetin act as reversible monoamine oxidase inhibitors and selectively binds with high affinity to the central benzodiazepine receptors possesses important antidepressant activity. Conclusion: The literature reveals that the main constituents of A. occidentale are flavonoids, quercetin, apigenin, tannins and alkaloids. It was possible that the extract exerted the antidepressant activity through interaction with adrenergic, dopaminergic, serotonergic and GABAnergic system.