Abstract: Tilapia were used as an alternative animal model for evaluating metabolic syndrome, e.g., hyperlipidaemia and hypercholesterolaemia. Vascular lipid accumulation and inflammation of tilapia were induced by a high-fat diet (HFD) given for two weeks. The HFD triggered lipid peroxidation, high concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol in plasma, leading to hyperlipidaemia, fatty liver, and lipid accumulation in aorta intima. Tilapia fed an HFD supplemented with freshwater clam extracts (FCEs) showed improved plasma lipid profiles, reduction of liver size and decreased lipid accumulation in the liver. FCEs also enhanced plasma antioxidant status and alleviated vascular lesions in the tilapia fed an HFD. In vivo experimental results proved the atherosclerosis-preventive properties of FCEs against oxidative stress on lipid metabolism. Consequently, FCEs may serve as a potential nutraceutical ingredient to reduce the risk factors of cardiovascular diseases.