Background: Diabetic cardiomyopathy (DCM) is a major cause of diabetes-related morbidity and mortality. Alpha lipoic acid (ALA) and Melatonin (Mel) have gained a considerable amount of attention as antioxidants, their effect on the progression of DCM has not yet determined. Aim: To evaluate effects of ALA and Mel on AMP-activated protein kinase (AMPK) activity and the state of oxidative stress (OS) in DCM in rats. It also aims at correlating the pathogenesis of DCM to AMPK activity. Methods: 60 rats were divided into 6 groups (n=10); control (CG), C + ALAG, C + MelG, Diabetic (DG), D + ALAG and D + MelG. Diabetes was induced by 60mg/Kg streptozotocin. ALA and Mel were given in a dose of 100 mg/kg/day and 10 mg/kg/day respectively for 12 weeks. The heart/body weight (Ht/BW) ratio, AMPK activity and oxidative state in cardiac tissue, serum cardiac enzymes (serum lactate dehydrogenase "LDH" and creatine kinase "CK"), lipid profile, fasting glucose level and histologic examination were assessed at the end of the study. Results: Ht/BW and OS increased in DG compared to CG, decreased subsequently by ALA and Mel treatment with no significant difference between both groups. LDH and CK were higher in DG as compared to CG. Cardiac AMPK activity was decreased in DCM and increased subsequently by ALA and Mel treatment. Normal cardiac architecture was restored by both of them. ALA and Mel showed a hypolipidemic effect while ALA had a hypoglycemic effect. Conclusions: ALA and Mel enhanced AMPK activity, and antioxidant activity in the heart thus decreased the progression of cardiac dysfunction.