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The cardiovascular and liver protection of carnitine (CNT) in a high-fat diet was investigated. Male C57BL/6 mice were divided randomly into four groups: 1) CON: Control, 2) HFD: high-fat diet, 3) CNTL: HFD + 500 mg CNT/kg BW, and 4) CNTH: HFD + 1500 mg CNT/kg BW. After a 25-week experimental period, CNT supplementation reduced (p < 0.05) serum triacylglycerol (TAG), cholesterol (TC) and LDLC/HDLC ratio, and liver TAG contents. CNT supplementation downregulated (p < 0.05) gene expressions of lipogenesis, but upregulated (p < 0.05) gene expressions of cholesterol clearance/catabolism and energy expenditure. Serum trolox equivalent antioxidants capacity (TEAC), and liver glutathione (GSH) contents and glutathione-peroxidase (GPx) activity of HFD fed mice were also increased (p < 0.05) by CNT supplementation. Besides, proinflammation related gene expressions (Tlr4 and Nfκb) and proinflammatory cytokine (TNF-α) contents in livers of HFD fed mice were also decreased (p < 0.05) by CNT supplementation. Furthermore, in comparison with the ameliorative effects of two-dosage CNT treatments on dyslipidemic and hepatic disorders induced by a high-fat diet, low dosage of CNT seems more effective than high dosage of CNT.