This study aimed to investigate the effects of tetrahydroxy stilbene glucoside (TSG) on diabetes mellitus (DM) combined with myocardial ischemia-reperfusion injury (MIRI) in rats. Forty rats were randomly divided into 4 groups including control, TSG, DM+MIRI and DM+MIRI+TSG groups, 10 rats in each group. The rats in TSG and DM+MIRI+TSG were intragastrically administrated with 60 mg/kg TSG. The DM combined with MIRI model was established in DM+MIRI and DM+MIRI+TSG groups. The cardiac function, myocardial infarct, blood glucose, oxidative stress indexes and myocardial cell apoptosis-related protein expressions were determined. Results showed that, compared with DM+MIRI group, in DM+MIRI+TSG group the percentage of myocardial infarction area, fasting plasma glucose, hemoglobin A1, fasting insulin, serum lactate dehydrogenase, creatine kinase-MB, and myocardial malondialdehyde, B-cell lymphoma-2 associated X protein, and cysteinyl aspartate specific proteinase-3 protein levels were significantly decreased, and the left ventricular systolic pressure, +maximum left ventricular systolic/diastolic rate (dp/dt(max)) and -dp/dt(max), serum glutathione peroxidase, and myocardial superoxide dismutase and B-cell lymphoma-2 protein expression levels were significantly increased (all P < 0.05). In conclusion, TSG can alleviate DM combined with MIRI in rats by resisting oxidative stress and inhibiting myocardial cell apoptosis.