ABSTRACT Background: Metabolic syndrome (MS) increases the risk of developing cardiovascular diseases (CVDs) which are the leading cause of death worldwide. Objective: This study is aiming to investigate the curative effects ofdipeptidyl peptidase-4 inhibitorsand the prophylactic effects of curcumin on diet induced metabolic syndrome which is associated with cardiac dysfunction in rats. Methodology:  sixty adult male albino rats were divided into six groups: Group I: (control). Group II: (MS induced). Group III: (Vildagliptin only). Group IV: (Curcumin only). Group V (therapeutic):Vildagliptin treated rats after 8 weeks of MS to the end of 12 weeks. Group VI (prophylactic): Curcumin is administered with MS induction concomitantly for 12 weeks. Transthoracic echocardiogram was done while rats were alive. At the end of the experiment, blood was collected and biochemical analysis (blood glucose, serum insulin, lipid profile and cardiac enzymes) was done. Heart tissues were used for oxidative stress parameters (cardiac mitochondrial reactive oxygen species (ROS) and cardiac mitochondrial complex I and complex II) beside histopathological examination. Results: High fat diet (HFD)administration resulted in a significant increase in blood glucose, serum insulin, homeostasis model assessment of IR (HOMA- IR) index with disturbed lipid profile. Significant increase in serum cardiac enzymes and oxidative stress tissue markers were also noticed. Echocardiography revealed structural and functional cardiomyopathy. Histopathological examination showed cellular infiltrations with fat cells and collagen fibers accumulation. DPP- 4 inhibitors and curcuminresulted in a significant decrease in glucose, insulin, and HOMA- IR index, partial amelioration of lipid profile, cardiac enzymes, and cardiac oxidative stress markers. Echocardiography revealed alleviation of cardiomyopathy. Histopathological examination also revealed highly manifested structural improvement. Conclusion: The current study revealed that both DPP- 4 inhibitors and curcumin improve cardiomyopathy resulted from HFD administration with a diversity of mechanisms including anti-inflammatory, anti-apoptotic and anti-oxidative ways.