〔Abstract〕 Objective To investigate the effects of polydatin on a high-fat diet-induced non-alcoholic fatty liver disease(NAFLD) mouse model and hepatoma G2(HepG2) cell model, and to reveal its potential molecular mechanisms. Methods Thirty 6-week-old male SPF C57BL/6J mice were randomly divided into a normal diet group and a high-fat diet group. After the NAFLD mouse model was established in the high-fat diet group, they were further divided into a model group and a polydatin treatment group. The polydatin treatment group was administered polydatin by gavage at a dose of 250 mg/(kg·d) for 10 weeks, during which body weight was monitored and oral glucose and insulin tolerance tests were performed. At the end of the experiment, a series of tests to evaluate the effects of polydatin on mouse liver weight, blood lipids, liver lipid accumulation, and liver injury markers were performed. The expression of G0/G1 switch gene 2(G0S2) and adipose triglyceride lipase(ATGL) was measured by qRT-PCR and Western blot, and gene expression was further verified using immunohistochemical staining. The effects of polydatin on HepG2 cell activity was assessed by CCK-8 assay, lipid accumulation was observed by oil red O staining, and the expression of G0S2 and ATGL was detected by qRT-PCR and Western blot. Results Polydatin significantly reduced the body weight, liver weight, and serum and liver tissue levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), triglyceride(TG), and total cholesterol(TC) in mice(P