AIM: To investigate the regulatory effects of silybin on hepatic lipid metabolism in mice with non -alcoholic steatohepatitis (NASH) induced by high - fat and high-cholesterol (HFHD) diet. METHODS: Mice were fed a HFHD diet to construct a NASH model, and serum levels of triacylglycerol (TAG), total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured using biochemical kits. H&E staining and oil red O staining were used to detect histopathological changes in the liver. Lipidomics was used to detect the alterations of hepatic lipid metabolism in NASH mice. RESULTS: Silybin significantly inhibited the increase of body weight, liver weight and abdominal fat, decreased serum T-CHO, TAG and LDL-C levels, improved hepatic lipid droplet accumulation and ballooning degeneration, and back-regulated hepatic palmitoleic acid (C16: 1) and polyunsaturated long-chain fatty acids (PUFAs) in NASH mice. CONCLUSION: Silybin possibly reduced hepatic lipid accumulation and lipotoxicity by modulating abnormal hepatic lipid metabolism in mice induced by HFHC diet.