Abstract: To evaluate the antidepressant activity of ethanolic extract of Piper betle leaves in mice, 48 adult albino mice (Swiss strain) weighing 25-30 g were selected. Twenty four animals were allocated to Forced Swim Test (FST) and 24 to Tail Suspension Test (TST) models. In each model there were 4 groups. The control group received vehicle (10 mL kg-1, p.o.), the standard, imipramine (10 mg kg-1, p.o.) and the two test groups received ethanolic extract of P. betle leaves (PBL) 100, 200 mg kg-1 p.o., respectively, 1 h prior to the acute study. In chronic study, the drugs were given orally once a day for 10 days and the last dose was given 1 h before the experiment. Duration of immobility was noted in FST and TST. Statistical analysis was performed using Mean±SEM and ANOVA followed by Dunnett’s test. The p<0.05 was considered statistically significant. Ethanolic extract of PBL produced significant antidepressant effect at both the doses (100, 200 mg kg-1), as indicated by reduction in the duration of immobility compared to the control. The antidepressant effect was higher at 100 mg than at 200 mg. In addition, the effect at 100 mg was greater than that of imipramine. Ethanolic extract of PBL thus has shown significant antidepressant activity greater than imipramine in mice.