Objective To observe the effect of hyolroxylsafflor(HSYA) on cyclooxygenase-2(COX-2)/ prostaglandin E₂(PGE₂) signaling pathway, and to investigate the protective effect and mechanism of HSYA on cerebral ischemia-reperfusion injury（CIRI）. Methods Totally 90 SD male rats were randomly divided into sham-operated group(S group), operation group(CIRI group), HSYA group and celecoxib group(C group), HSYA group subdivided into HSYA low dose group(HSYA-L group), HSYA medium dose group (HSYA-M group)and HSYA high dose group(HSYA-H group), 15 rats in each group. CIRI model was prepared by thread embolism method. The rats in each group were given intraperitoneal injection 30 minutes before operation. HSYA groups were given HSYA 10 mg/kg, 15 mg/kg, 25 mg/kg respectirely; C group was given celecoxib 40 mg/kg; S group and CIRI group were given the same amount of normal saline. Neurofunctional scores of each group of rats were performed immediately after recovery from modeling, cerebral infarction volume was measured 24 hours after reperfusion; At the same time, neuronal injury was observed by Nissl staining, the changes of COX-2 mRNA and protein were detected by Real-time PCR and Western blotting, and the changes of PGE₂, tumor necrosis factor α(TNF-α) and interleukin(IL)-1β were detected by ELISA.   Results  Compared with the S group, in the CIRI group, neurofunctional scores increased dramatically (P<0.05), the volume of cerebral infarction increased dramatically (P<0.05), the damage of neurons increased and the number of neurons decreased dramatically (P<0.05), the expressions of COX-2 mRNA and protein increased dramatically (P<0.05), meanwhile the expressions of PGE₂, TNF-α and IL-1β were also found dramatically increased (P<0.05); Compared with the CIRI group, in the HSYA group and C group, neurofunctional scores decreased dramatically (P<0.05), the volume of cerebral infarction was reduced dramatically (P<0.05), the damage of neurons decreased and the number of neurons increased dramatically (P<0.05), the expressions of COX-2 mRNA and protein, PGE₂, TNF-α and IL-1β decreased dramatically(P<0.05). The differences between HSYA groups and both HSYA-L group and HSYA-M group compared with the C group were obvious(P<0.05), while no obvious differences were found in HSYA-H group compared with the C group(P>0.05). Conclusion  HSYA alleviates reperfusion injury in ischemic stroke may be related to the inhibition of COX-2/PGE₂ signaling pathway.