Paeoniflorin (PF) is the major bioactive constituent of peony root, which has been used to treat depressive patients in Traditional Chinese Medicine.However, whether or not PF has antidepressant effects, and if so, what may be the underlying mechanism, remain unclear.The main goal of the present work was to evaluate the antidepressant effects of PF (i.p.) in various rodent animal models of depression, including the forced swimming test (FST), the novelty-suppressed feeding (NSF) test and the chronic mild stress (CMS) paradigm, and its possible mechanisms underlying the behavioral changes.The results show that acute PF treatment significantly decreases the total time of immobility in the FST, and the latency in the NSF test is also decreased after 7-d PF injection in adult mice.These effects are also observed 7 d after PF administration and last up to 1 month.Importantly, 2-week administration of PF (1.0 mg/kg per day) reverses the anhedonia in rats exposed to a 7-week CMS protocol.In this respect, the effect of PF was similar to the effect of imipramine (20 mg/kg per day), and even showed more rapid onset of action than them.In addition, our findings demonstrate that there are more newborn cells in the hippocampus in PF-treated animals, and most of them are differentiated into neuron.Moreover, acute PF treatment significantly increases BDNF and VEGF expression in the hippocampus.Together, these results suggest that PF is able to enhance adult neurogenesis and produce rapid onset of antidepressant-like effects, while BDNF or/and VEGF signaling may be involved in the mechanism of the antidepressant effect of PF.