Background: Diabetes is associated with both micro- and macrovascular complications. Aim of the study: The aim of the present study is to evaluate the prophylactic effect of HCQ alone and in combination with glimepiride and metformin on ISO induced MI in type 2 diabetic rats. The present study included the parameters blood glucose, plasma insulin, HOMA-IR index, lipid profile, AKT, ECG changes and histopathology of the myocardium. Methods: Rats were classified into: Group I: control normal group. Group II: was not treated diabetic (diseased group). Group III: was treated with HCQ. Group IV: was treated with glimepiride. Group V: was treated with metformin. Group VI: was treated with HCQ + glimepiride. Group VII: was treated with HCQ + metformin. treated groups received drugs for 4 weeks. Results: Treated groups showed significant improvement in all parameters and improvement of the histopathology of the myocardium. A significant improvement in the parameters was seen in the treated groups at the end of the 4th week. Conclusion: Our study revealed that HCQ with glimepiride or with metformin produced more improvement in blood glucose level, insulin, HOMA-IR, lipid profile, AKT, ECG changes, histopathology of the myocardium. So, our drugs, mainly combined drugs may have a prophylactic effect against MI in diabetic rats. this may be due to their glycemic control and improvement of dyslipidemia.