Quercetin plays an important role in myocardial ischemia and reperfusion injury (IRI). However, the underlying mechanism for the protective effect of quercetin is largely unclear. In this study, we explored the protected effects of quercetin against myocardial IRI and its molecular mechanisms. Quercetin, GW9962 (PPARγ antagonist) or PPARγ-siRNA was administered alone or in combination prior to myocardial IRI in mice or to hypoxia and reoxygenation (H/R) treatment in H9C2 cells. Infarct size was evaluated by TTC staining after reperfusion. Myocardial injury was assessed by the serum levels of AST, CK-MB, cardiac troponin T (cTnT) and LDH. Cardiac function was measured by echocardiography. Oxidative stress injury was evaluated by analyses of inducible nitric oxide synthase (iNOS), MDA, SOD and glutathione peroxidase (GSH-PX) levels and by reactive oxygen species (ROS) detection. Myocardium apoptosis was evaluated by TUNEL staining, cleaved caspase-3 and Annexin V/PI detection. Moreover, activation of the NF-κB pathway was reflected by phosphorylation of IκB (p-IκB) and nuclear translocation of NF-κB p65. We reported that pretreatment of quercetin significantly improved cardiac function, diminished myocardial injury and reduced the infarct size. Myocardium oxidative damage and apoptosis were remarkably improved by quercetin treatment in vivo and . Quercetin also suppressed the activation of the NF-κB pathway induced by myocardial IRI. GW9662 or PPARγ knockdown partially attenuated these cardioprotective effects of quercetin during myocardial IRI. In conclusion, our findings suggest that quercetin ameliorated IRI-induced heart damage via PPARγ activation and the underlying mechanism might involve the inhibition of NF-κB pathway by PPARγ activation.