We have developed a novel rodent animal model of reperfusion injury following stroke. In this model, blood flow through the middle cerebral artery (MCA) is temporarily occluded by placing gentle pressure on sutures behind the artery along three separate branches. The sutures remain in place for a period of time (occlusion), and are then removed for an additional amount of time (reperfusion) to study the effects of drug treatment on the ischemic core and/or reperfusion injury. This approach resulted in a highly reproducible focal infarct restricted to the prefrontal cerebral cortex with an intra-operative mortality rate of less than 1%. To validate this new model of reperfusion injury, we used two well characterized neuroprotectants, estrogen and edaravone. Estrogen and edaravone have been studied extensively in many animal models, and our lab as well as others have consistently demonstrated significant reductions in infarct size following edaravone or estrogen pretreatment. In this novel model, intravenous pretreatment of animals with either estrogen or edaravone resulted in significant, dose-dependent, reduction in infarct size following reperfusion. In conclusion, our results demonstrate the validity of using this novel model to study the mechanism of neuroprotection following stroke. Based on the low mortality rate and reproducibility of the focal infarct volume, this novel rodent model is ideal for preclinical studies to screen drugs for potential therapy against reperfusion injury following stroke.