To explore the effects of DHA liposomes on lipid metabolism, HepG2 cells were induced by free fatty acids. After the intervention of DHA liposomes, the contents of TG and TC were detected. The mRNA expression of Fatty acid synthase (FAS) and Sterol regulatory element binding protein 1 (SREBP-1) were detected by RT-PCR. Then male C57BL/6J mice (6 weeks old) were housed and randomly devided into control group (C), model group (M), TG-DHA emulsion (O-DHA), TG-DHA liposome (L-DHA). After 12 weeks, the protein expression levels of FAS, CPT-1 were determined by immunohistochemistry, the enzyme activity of Fatty acid synthase (FAS), malic enzyme (ME), carnitine palmitoyltransferase 1 (CPT-1), lipoprotein esterase (LPL) were detected using ELISA. The results showed that DHA liposomes significantly reduced the TC and TG contents (p<0.05) by 62.91% and 48.73% respectively; significantly reduced the mRNA expression levels of FAS (48.62%) and SREBP-1 (38.53%) (p<0.05). The results of animal experiments showed that DHA liposomes significantly reduced theepididymal fat content (14.26%) of high-fat diet mice (p<0.05); significantly reduced the protein expression levels of FAS (74.29%) (p< 0.05) and increased the protein expression levels of CPT-1 (1.70 folds) (p<0.05). DHA liposomes could significantly inhibited the activities of FAS, ME (p<0.05), reduced by 30.33% and 11.79% respectively; and promoted the activities of CPT-1, LPL (p<0.05), increased by 10.08% and 15.12% respectively. This study showed that DHA liposomes can improve lipid metabolism disorder induced by high-fat diet, and provide theoretical basis for the development and utilization of deep-sea fish oil.