The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect on brain injury after focal cerebral ischemia reperfusion, and to determine the possible mechanism. Behavioral tests were used to evaluate the damage to central nervous system. The infarct volume of brain was assessed in brain slices stained with 2% solution of 2,3,5-triphenyl tetrazolium chloride (TTC). Adult male Wistar rats were subjected to 2h of middle cerebral artery occlusion and 24h of reperfusion. Spectrophotometric assay was used to determine the content of malondialdehyde (MDA), and the activity of total antioxidative capability (T-AOC) and superoxide dismutase (SOD). The results showed that treatment with HSYA (2, 4, 8 mg/kg, i.v.) significantly decreased neurological deficit scores and reduced the percentage of infarction in the ipsilateral hemisphere compared with the model group. At the same time, HSYA treatment significantly attenuated the elevation of MDA content, the decrease in SOD activity, and the T-AOC in the ipsilateral hemisphere and serum. All of these findings suggest that HSYA might provide neuroprotection against cerebral ischemia/reperfusion injury through its antioxidant action.