OBJECTIVES: Tiaogan Jiejiu Tongluo formula (TJTF) is a traditional Chinese medicine formula for liver disease. The purpose of this study was to explore the protective effects and mechanisms of TJTF on nonalcoholic fatty liver disease (NAFLD) mice. METHODS: A NAFLD model of mice was established by a combination of a high-fat diet and CCL4 and then treated with TJTF. The damage to liver tissue was observed through histopathology, and the levels of AST, ALT, TG, TC, LDL-C, and HDL-C in the serum, as well as SOD, GSH, and MDA in the liver tissue were determined using biochemistry or ELISA kit. The expression of proteins related to the AMPK pathway was detected by western blotting. RESULTS: Biochemical indicators and pathological examination showed that TJTF could enhance the antioxidant capacity of liver tissue and significantly reduce liver lipid deposition. In addition, TJTF significantly increased levels of LKB1 and p-AMPK, and decreased the levels of HMGCR, SREBP-1c, FAS, and ACC. CONCLUSION: TJTF can alleviate hepatic steatosis and effectively improve NAFLD by regulating AMPK signaling pathway in NAFLD mice.