To further explore the underlying antidepressant mechanism of ginseng total saponins (GTS), this study observed the effects on hippocampal astrocyte structural plasticity and hippocampal volume in the corticosterone-induced mouse depression model. Corticosterone (20 mg/kg/day) was administered subcutaneously for 5 weeks, and GTS (12.5, 25, and 50 mg/kg/day; namely GTSL, GTSM, and GTSH) or fluoxetine (10 mg/kg/day) were given intragastrically during the last 3 weeks. On day 33 and day 34, 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 35), all mice were sacrificed followed by serum corticosterone assays, stereological analysis of hippocampal glial fibrillary acidic protein-positive (GFAP+) astroctyes and hippocampal volume, and hippocampal glycogen tests. Results showed that all doses of GTS ameliorated depression-like behavior and the decrease in hippocampal glycogen without normalizing hypercortisolism. Moreover, GTSH and GTSM reversed the corticosterone-induced reduction in the total number of hippocampal GFAP+ astrocytes and hippocampal volume. Additionally, GTSH alleviated the diminished protrusion length and somal volume of GFAP+ astrocytes induced by corticosterone. These findings imply that the effects of GTS on corticosterone-induced depression-like behavior may be mediated partly through the protection to hippocampal astrocyte structural plasticity.