Background <p>Nonalcoholic fatty liver disease (NAFLD), particularly the histological phenotype nonalcoholic steatohepatitis (NASH), is considered the primary cause of chronic liver diseases. Shugan Xiaozhi decoction (SX), a composite Chinese medicinal formula, has shown therapeutic potential for NASH, although the underlying mechanisms remain incompletely defined. In this study, the effects and mechanisms of SX in rats with NASH and fibrosis induced by a high-fat and high-cholesterol (HFHC) diet were investigated.</p> Methods <p>NASH rats with fibrosis were induced by an HFHC diet, with different doses of SX administered. Biochemical indices, histological changes, and gene expression were assessed to evaluate lipid metabolism, inflammation, fibrosis of the liver. The histological changes of white and brown adipose tissue were also determined. Hepatic transcriptomics and network pharmacology based on the blood components were employed to elucidate the biological processes and signaling pathways, which was subsequently verified, and the material basis of SX was investigated through docking simulations.</p> Results <p>SX treatment effectively corrected disordered lipid profiles, mitigated hepatic phagocyte infiltration, and alleviated damage in the white and brown adipose tissues. It also downregulated the expression of NLRP3, caspase-1, IL-1β, α-SMA, Col1a1, and TGF-β, to improve hepatic inflammation and fibrosis. Mechanistically, transcriptomics and network pharmacology analyses revealed that SX ameliorated hepatic oxidative stress and activated the AMPK pathway, and the downstream effector Nrf2 and inactivated of SREBP1/FAS signaling. Three putative phytochemicals, namely, gallic acid, protocatechuic acid, and rhein with the highest binding affinity for AMPKα were also identified.</p> Conclusions <p>SX ameliorates HFHC diet-induced NASH by regulating hepatic oxidative stress and AMPK pathway, suggesting the potential therapeutic value of SX in NASH treatment.</p> Graphical Abstract <p></p>