Objective To establish a rat model of nonalcoholic fatty liver disease (NAFLD) and observe the effect of Dendrobium nobile polysaccharide on the expression of cytochrome P4502E1 protein and mRNA. 〖WTHZ〗Methods〖WTBZ〗 60 male SD rats of SPF grade were randomly divided into normal group, model group, polyene phosphatidylcholine group, Dendrobium nobile polysaccharide low, medium and high dose group, 10 rats in each group. The model of nonalcoholic fatty liver disease was established by high fat and high sugar diet. After 6 weeks of treatment, the general situation of rats was observed, the liver pathology, the expression of CYP2E1 protein and mRNA in liver tissue were detected, and the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol (TC), triglyceride (TG), catalase (CAT) and superoxide dismutase (SOD) in blood were detected. Results In the model group, there was a certain degree of fatty degeneration, and some hepatocytes were infiltrated with inflammatory factors. Compared with the model group, each treatment group improved. Compared with the normal group, the liver index, AST, ALT, TG, TC, CYP2E1 protein and mRNA in the model group increased significantly, while CAT and SOD decreased significantly (P＜0.05). Compared with the model group, AST, ALT, TG, TC, CYP2E1 protein and mRNA in the three dose groups of Dendrobium nobile polysaccharide and polyene phosphatidylcholine group were significantly lower (P＜0.05), CAT and SOD were significantly higher (P＜0.05), and TG and TC in the high dose group of Dendrobium nobile polysaccharide were significantly lower than those in the polyene phosphatidylcholine group (P＜0.05). The protein and mRNA of CYP2E1 in three dosages of Dendrobium nobile polysaccharide group were significantly lower than those in polyene phosphatidylcholine group (P＜0.05). Conclusion Dendrobium nobile polysaccharide can significantly reduce the expression of CYP2E1 protein and mRNA in the liver of NAFLD rats, improve the liver function and blood lipid level, improve the activity of cat and SOD, and finally effectively alleviate the symptoms of NAFLD rats.