The antidepressant-like effect of trans-resveratrol, a phenolic compound present in polygonum cuspidatum, was evaluated through behavioral and neurochemical methods. trans-Resveratrol (20, 40 and 80 mg/kg, via gavage) significantly decreased the immobility time in mouse models of despair tests, but did not influence locomotor activity. Two behavioral models and neurochemical assays suggested that trans-resveratrol produced a significant increase in serotonin and noradrenaline levels at 40 or 80 mg/kg in brain regions. In addition, trans-resveratrol dose dependently inhibited MAO-A activity. These findings indicate that the antidepressant-like effect of trans-resveratrol might be related to serotonergic and noradrenergic activation.