Ginseng total saponins (GTS) are the major active components of Panax ginseng C.A. Meyer, which has been used as a popular tonic herb for 2000 years in Far East countries. In the present study, two classic animal models: the forced swimming test (FST) and the chronic mild stress (CMS) model were used to evaluate the antidepressant-like activities of GTS. It was observed that GTS at doses of 50 and 100 mg/kg significantly reduced the immobility time in the FST in mice after 7-day treatment. GTS also reversed the reduction in the sucrose preference index, decrease in locomotor activity as well as prolongation of latency of feeding in the novelty environment displayed by CMS rats. In addition, HPLC-ECD and immunohistochemical staining analysis indicated that the CMS-induced decrease in monoamine neurotransmitter concentration and brain-derived neurotrophic factor (BDNF) expression in the hippocampus were almost completely reversed by GTS. In conclusion, GTS exerts antidepressant-like effects in two highly specific and predictive animal models of depression. The activity of GTS in antidepression may be mediated partly through enhancing the monoamine neurotransmitter concentration and BDNF expression in the hippocampus.