Abstract: OBJECTIVE To study the protective effects of formononetin (FOR) on cerebral ischemia-reperfusion injury (I/R) in rats and explore its possible mechanism. METHODS Fifty male SD rats were divided into 5 groups:sham operation group, I/R group, FOR high, medium and low dose group (100, 50, 20 mg·kg^-1). Continuous intragastric administration for 7 d, MCAO model was used to make I/R rats. After 2 h, plug was pulled out and after 24 h blood were perfused to form the model of I/R, the neurological score was detected;the ability of learning and memory was detected by step-down test;pathological morphology was observed by HE;NO expression and NOS activity in serum was detected by ELISA;the expression of caspase-3, Bcl-2 and Bax protein in brain tissues was detected by Western blot method. RESULTS Compared with I/R group, FOR high, middle and low dosage groups could significantly reduce the rat nerve function score (P<0.01), improve the ability of learning and memory of rats (P<0.05 or P<0.01), improve the morphology of brain tissue, decrease the NOS activity level and expression of NO in serum (P<0.01), reduce caspase-3 and Bax protein expression level and improve the expression level of Bcl-2(P<0.01). CONCLUSION It is possible that FOR can protect I/R rats, and its mechanism maybe related to anti-oxidative stress and anti-apoptosis.