Ginseng total saponins (GTS) are principal bioactive ingredients of Panax ginseng. In this study, we investigated the antidepressant effect of GTS on the corticosterone-induced mouse depression model and explored the underlying mechanism. Corticosterone (20 mg kg−1 d−1) was subcutaneously administered for 22 d to induce the model, before doses of GTS (12.5, 25, and 50 mg kg−1 d−1) or fluoxetine (10 mg kg−1 d−1) were subsequently given by gavage. On day 20 and 21, depression-like behavior was observed via a forced swimming test and a tail suspension test respectively. At 6 h after the last dose of corticosterone (day 22), all mice were sacrificed followed by serum corticosterone assays and Western blot analysis. The results showed that GTS (25 and 50 mg kg−1 d−1) treatments relieved depression-like behavior without altering the elevated serum corticosterone levels. Furthermore, GTS treatments raised the down-regulated levels of hippocampal glycogen synthase kinase-3β (GSK-3β) inhibitory phosphorylation. In contrast, fluoxetine (10 mg kg−1 d−1) treatment reversed the increased corticosterone level and had no effect on the decreased GSK-3β inhibitory phosphorylation. These findings confirmed the antidepressant effect of GTS in the corticosterone-induced mouse depression model. Enhancing GSK-3β inhibitory phosphorylation may be one of the underlying mechanisms. Copyright © 2013 John Wiley & Sons, Ltd.