The objective of this study was to estimate the protective influence of sevoflurane preconditioning on myocardial ischemia-reperfusion (IR) injury. Rat models of myocardial IR and sevoflurane preconditioning were built. The area of myocardial ischemia and infarction were estimated via Evan blue and TTC double staining. The histopathological changes of heart tissues were examined using a hematoxylin & eosin staining kit. TUNEL assay was applied to detect cardiomyocyte apoptosis and calculate the apoptosis rate. The concentrations of ERS related molecules GRP78 and CHOP in the myocardium were estimated via real-time fluorescent quantitative PCR. The GRP78, CHOP, caspase-3, caspase-12, Bax and Bcl-2 concentrations in the myocardium were estimated via western blot. ROS, MDA and SOD were assessed. The concentration of HIF-1 α and its downstream gene inducible nitric oxide synthase (iNOS) and cGMP concentration in myocardial tissue were estimated. Sevoflurane preconditioning lessened the size of myocardial infarction induced via ischemia/reperfusion(P<0.05), lessened cardiomyocyte apoptosis and oxidative stress (P<0.05), enhanced the concentration of HIF-1 α and enhanced the concentration of iNOS and cGMP concentration in myocardium (P<0.05). After administration of HIF-1-α proline hydroxylase inhibitor DMOG, the concentration of HIF-1-α enhanced after sevoflurane preconditioning (P<0.05), the concentration of iNOS and cGMP enhanced (P<0.05). Meanwhile sevoflurane preconditioning protective influence on myocardial injury was also further enhanced (P<0.05). Sevoflurane preconditioning protective influence on myocardial injury induced via ischemia/reperfusion may be related to the activation of the HIF-1 α / iNOS/cGMP pathway in myocardial tissue.