Abstract: Objective To investigate the effect of Hugan Qingzhi tablets on lipid metabolism and inflammation in rats fed on high-fat diet and explore the underlying mechanisms. Methods Sixty male Sprague-Dawley rats were randomly divided into 6 groups, namely HFD group (with high-fat diet and distilled water), control group (with normal diet and distilled water), fenofibrate group (with high-fat diet and treatment with 0.1 g/kg fenofibrate suspension), and low-, moderate- and high-dose Hugan Qingzhi tablet groups (with high-fat diet and treatment with 0.54, 1.08, and 2.16 g/kg Hugan Qingzhi suspension). After daily corresponding treatments for 12 weeks, the histological changes in the liver were observed with HE staining. The serum levels of triglyceride (TG), cholesterol (CHOL), alanine transaminase (ALT), and aspartate aminotransferase (AST), and the levels of TG and CHOL in the hepatic tissue were assayed. The proinflammatory cytokines TNF-α, IL-6 and CRP were detected with enzyme-linked immunoassay, and p-AMPK, SREBP-1c, FASN and NF-κB-p65 expression levels in the liver were determined with qRT-PCR or Western blotting. Results At high and moderate doses, Hugan Qingzhi effectively decreased the levels of ALT, AST, TG and CHOL levels in the serum, lowered the hepatic levels of TNF-α, IL-6 and CRP, enhanced p-AMPK, and reduced the expression of SREBP-1c, FASN and Ac-NF-κB-p65 in the liver of rats fed on high-fat diet. Conclusion Hugan Qingzhi tablets alleviates hyperlipidemia and inflammation in rats fed with high-fat diet possibly by activating AMPK pathway and suppress NF-κB activity to arrest the progression of nonalcoholic fatty liver disease.