Objective To explore the antidepressant effects of low dose fisetin combined with piperine and its possible mechanism. Methods The tail suspension test and the forced swimming test were used to explore the antidepressant ef-fects of low dose fisetin combined with piperine. In addition, the locomotor activity test was used to exclude the false positive effect in behavioral despair tests. High performance liquid chromatography (HPLC) was used to determine the expression of monoamine. The monoamine oxidase activity in the mouse brain was also determined by fluorospec-trophotometry. Results The results showed that fisetin (1.25 mg/kg, 2.5 mg/kg and 5 mg/kg, ig) combined with piperine (2.5 mg/kg, ip) significantly reduced the duration of immobility in both tail suspension and forced swimming tests. The effective doses did not alter locomotor activity. Moreover, neurochemical assays showed that its produced an increase in monoamine levels in the hippocampus, fronal cortex and amygdala. Monoamine oxidase (MAO) activity in the mouse brain was inhibited while MAO-B activity was not affected. Conclusion These findings suggestde that low dose fisetin combined with piperine exerted antidepressant effect in behavioral despair tests and the underlying mechanism may in-volve the inhibition monoamine oxidase activity in the mouse brain.