ABSTRACT Background: Diabetic cardiomyopathy (DCM) is a cardiac disorder that could progress to heart failure. There is conflicting data about the role of folic acid supplementation in treatment DCM. Aim: This study was performed to compare between the protective and therapeutic effects of folic acid on ECG and structural changes of DCM rat model. Materials & Methods: Sixty rats were divided as follows: Normal control groups (Ia and Ib), DCM groups (IIa and IIb): Fed high fat diet for 4 weeks then injected with streptozotocin (25 mg/kg/ i.p), and folic acid treated groups (IIIa and IIIb): rats received 5 mg/kg/day orally for 8 weeks from first day of confirmation of diabetes in rats in group (IIIa), and from the end of 7th week after confirmation of diabetes in rats in group (IIIb). ECG, blood pressure, lactate dehydrogenase, Creatine kinase-MB, soluble receptor of advanced glycation end products (sRAGE), oxidative stress (OS) and inflammatory markers were assessed. Histopathological analysis of left ventricular tissue using Hematoxylin & eosin, Masson’s Trichrome stains, and immunohistochemical analysis of Caspase3 and iNOS expression were performed. Results: A significant improvement in R wave amplitude, ST segment deviation and a reduction in sRAGE in folic acid protective not therapeutic group were found when compared to untreated DCM group. Moreover, cardiac enzymes, histopathological changes, collagen fiber deposition, oxidative stress (OS), inflammation, and apoptosis significantly improved in both folic acid treatment groups when compared to untreated DCM groups. Conclusion: The protective role of folic acid on cardiac injury in DCM rat model was more effective than the therapeutic ones that could be attributed to better glycemic, OS control and amelioration of AGE/RAGE signaling and improvement in cardiac structural changes. Key words: Diabetes mellitus, folic acid, cardiomyopathy, apoptosis, oxidative stress.