Abstract Kami-shoyo-san (KSS), a traditional Chinese medicine, has been used to treat patients with neuropsychiatric disorders. The aim of the present paper was to investigate whether KSS has antidepressant-like effects, and to assess its mechanism of action, using male Sprague–Dawley rats given 10-fold (KSS 10X) or 20-fold (KSS 20X) the typical human daily dosage. Immobility time was measured by the forced swimming test, and hippocampal neurogenesis was quantified under immobilization stress. Rats given KSS 20X, but not those given KSS 10X, had a significantly lower immobility time and improved neurogenesis in the hippocampus. These results suggest that KSS possesses an antidepressant-like effect at a behavioral and molecular level.