In our pilot study, the depressive-like behaviors of mice exposed to cerebral ischemia reperfusion (CIR) were observed and the antidepressant effects of radix puerariae (RP; root of the Pueraria plant) extract in CIR mice were assessed because it was speculated that the neuronal damage caused by CIR played an important role in the development of poststroke depression (a common and severe complication after stroke) and the RP extract was reported to exhibit effect of neuronal protection from cerebral ischemia damage. Our studies above indicated that the RP extract markedly shortened the increased immobility time induced by CIR of male mice in the forced swimming test (FST) and tail suspension test (TST), indicating a possible antidepressant activity. Thus, the aim of the present study was to confirm the putative antidepressant effect of RP extract (75, 150, and 300 mg/kg, administered orally 24 h after the CIR) on reserpine-induced symptoms. To get further insight into the mode of antidepressant action of RP extract, biochemical examination was conducted concomitantly to examine possible involvement of the brain monoamine systems in the behavioral syndromes observed. In CIR mice, pronounced low levels of norepinephrine (NE) and 4-dihydroxyphenylacetic acid (DOPAC, a metabolite of dopamine) in the hippocampus or striatum were detected, which were reversed by RP extract, whereas no significant change of serotonin (5-HT) was detected in either CIR or RP extract-treated mice. The data suggested that the disturbance of NE and DA systems in hippocampus and striatum played more important roles in the development of depressive-like behavior of CIR mice than 5-HT system did, and RP extract ameliorated the abnormal symptoms caused by CIR, which may throw new lights on the treatment of poststroke depression.