In the present study, the myocardial protective effects of erythropoietin (EPO) by inhibition of the expression of caspase-12 were investigated in a myocardial infarction rat model. Thirty male SD rats were divided into three groups: sham-operation group, myocardial infarction group and EPO treatment group. The myocardial infarction model was created by ligating the left anterior descending coronary artery. The EPO treatment group was established by injecting rh-EPO (1,000 IU/kg) intraperitoneally every day after the operation, and the other two groups were injected with sodium chloride. Four weeks after induction of myocardial infarction, the left ventricular diastolic pressure (LVDP) was tested by Langendorff apparatus and the pathological changes were analyzed by H&E staining. Caspase-12 expression in the left ventricular myocardium was also measured by immunohistochemistry. Four weeks after induction of myocardial infarction, the improvement in heart function in the EPO treatment group was more distinct compared to that of the myocardial infarction group; LVDP was higher in the EPO treatment group compared to the myocardial infarction group, but lower compared to the control group. H&E staining showed that the myocardial cells in the normal control group were aligned in order with a clear structure and were stained equably, while the myocardial cells in the myocardial infarction model rats lined up in disorder with an augmented cell body appearing to have many granules and interstitial fibrosis. Myocardial fibrosis and disorder were improved in the EPO treatment group. The expression of caspase-12 in the myocardial infarction group was also increased compared to the EPO treatment group rats. The results suggest that EPO improves heart function in myocardial infarction rats by down-regulating the expression of caspase-12, which may protect the myocardium by abrogating endoplasmic reticulum stress-mediated cardiomyocyte apoptosis and improving heart function.