Stress exposure activates the sympathetic nervous system. We previously reported that restraint stress and stress-related neuropeptides increases plasma catecholamine levels and that brain prostanoids medicate these responses in rats. Yokukansan (YKS), a traditional Japanese medicine, has been used for neurosis, night crying and irritability. Additionally, it has been reported that YKS is also effective against the behavioral and psychological symptoms of dementia in patients with Alzheimer‘s disease, stress-related anxiety-like behavior and stress-induced increase in plasma corticosterone in rodents. These previous findings raise the possibility that YKS can exert its action in the brain and has suppressive effects on stress responses. In this study, we examined effects of YKS on stress-induced sympathetic activation and stress responses in the brain using rats. Repeated administration with YKS suppressed stress-induced increase in plasma adrenaline level. YKS also suppressed stress-induced elevation of prostaglandin E₂ and thromboxane B₂ levels in the paraventricular hypothalamic nucleus (PVN). In addition, YKS suppressed stress-induced increases of acetylcholine, GABA and serotonin in the PVN. Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain.