Studies have shown that the NRF-2 /HO-1 pathway participates in myocardial ischemic reperfusion injury (MI/R) and that Geniposide (GEN) could protect the myocardial against MI/R. This study aims to examine the protective effects of GEN on MI/R in diabetic rats and further explore the possible mechanism of action. During MI/R in rats, NRF-2 /HO-1signals changed significantly including NRF-2 and HO-1up-regulation, resulting in heart dysfuction, histological damage and increasing oxidative stress and cell apoptosis. Treatment with GEN can significantly improve the general condition and heart function in diabetic rats with decreasing the expression of cTnI, CK-MB, blood glucose, MDA, ROS, cell apoptosis and pathological damage in MI/R. In addition, GEN precondition can also significantly increase the weight of rats and the activity of SOD, CAT and GPx with up-regulating the expression of NRF-2 and HO-1 in MI/R. This study implied that Geniposide has a protective effect on myocardial ischemia reperfusion injury in diabetic rats, and its mechanism is associated with activating NRF2/HO-1 signaling pathway to suppress oxidative stress.