Aim To confirm the protective effect of cordycepsmilitaris polysaccharide (CMPS) on nonalcoholic fatty liver disease (NAFLD) in ApoE－/－ mice fed with high-fat diet and explore the underlying mechanism. Methods32 ApoE－/－ mice were randomly divided into ApoE－/－group and CMPS (5,0, 100 μg/g) treatment groups, all of which were fed with high-fat diet. The treatment groups were simultaneously fed with respective doses of CMPS. Another 8 C57BL/6 mice were fed with chow diet as control group (WT group). After 12-weeks experimental period, the mice were sacrificed. The liver index of mice was calculated and the histological changes of liver were observed by HE staining. The serum triglyceride (TG) concentration, liver TG concentration, superoxide dismutase (SOD) activity and lipid peroxide (LPO) content were detected according to the kit instructions. The levels of peroxisome proliferator-activated receptor α (PPARα) and acyl-CoA oxidase 1 (ACOX1) were analyzed by quantitative PCR and Western blot. Results Compared with ApoE－/－ group, CMPS treatment significantly reduced liver weight and liver index, alleviated hepatic steatosis induced by high-fat diet, and reversed the increasement of TG levels in liver and serum. Meanwhile, the mRNA and protein expressions of PPARα and ACOX1 were up-regulated in liver of CMPS treatment groups compared with those of ApoE－/－group. In addition, CMPS treatment enhanced the activity of SOD and lowered the content of LPO in the liver of ApoE－/－ mice. Conclusion CMPS can effectively improve NAFLD induced by high-fat diet in ApoE－/－ mice, which may be related to its promotion of fatty acid oxidation and inhibition of oxidative stress.