The current study aimed to examine the effects of propofol on myocardial ischemia-reperfusion injury (MIRI) in rats with type-2 diabetes mellitus (T2DM) and to assess the role of inflammatory mediators. Fifty healthy male adult Sprague-Dawley rats were randomly divided into the sham, ischemia-reperfusion (IR), IR plus low, middle and high-dose (6, 12 and 24 mg/kg/h, intravenous) propofol groups. The rats of all the groups were fed a high-sugar and high-fat diet for 8 weeks and streptozotocin (30 mg/kg, intraperitoneally) was used to establish the T2DM model. Apart from the sham group rats, MIRI was induced by ligating the left anterior descending coronary artery for 30 min, followed by reperfusion for 2 h. Heart rate (HR), left ventricular systolic pressure (LVSP), and the rate of left ventricular pressure increase in early systole (+/- dp/dt(max)) were recorded. Levels of cardiac troponin T (cTnT), nitric oxide (NO), endothelin-1 (ET-1), interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)- were also measured. Myocardial lesions were observed under light microscopy and scanning electron microscopy. Compared with levels prior to arterial occlusion, HR, LVSP, and +/- dp/dt(max) were significantly reduced (P<0.05) following occlusion for 30 min and reperfusion for 2 h. The administration of propofol ameliorated the cardiac function of rats as reflected by the increase in HR, LVSP and +/- dp/dt(max). In addition, the administration of propofol increased the serum NO concentration, and reduced ET-1 and cTnT levels, as well as levels of inflammatory mediators including IL-1, IL-6 and TNF-. Thus, propofol exerts protective effects against MIRI in T2DM rats by increasing NO and reducing ET-1 and the inflammatory mediators.