The effects of gypenosides (GPS) on electric footshock (EF)-induced acute stress in mice were investigated. Mice were treated orally with GPS (30-400 mg/kg) once a day for 5 days. After 2 days of GPS treatment, mice were exposed to EF stimuli (intensity, 2 mA; interval, 10 s; duration, 3 min) for acute stress for 3 days. Spontaneous locomotor activity was increased by acute EF stress, which was decreased by treatment with GPS (100 and 400 mg/kg). In addition, the increased levels of dopamine and serotonin by acute EF stress in the brain were reduced by treatment with GPS (100 and 400 mg/kg). The serum levels of corticosterone increased by acute EF stress were also reduced by GPS (100 and 400 mg/kg). These results suggest that GPS shows the ameliorating effects on acute EF stress by modulating the activity of dopaminergic and serotonergic neurons, and the serum levels of corticosterone. Clinical trials of GPS need to be conducted further so as to develop promising anti-stress agents.