BACKGROUND AND PURPOSE Alcohol-associated liver disease (ALD) caused by chronic alcohol consumption range from simple steatosis to alcoholic hepatitis, fibrosis, and cirrhosis. Physcion is an anthraquinone compound of Rheum palmatum L, a Chinese herbal medicine with possible hepatoprotective properties. This study aimed to investigate the protective effect and associated molecular mechanisms of physcion on chronic alcoholic liver injury. EXPERIMENTAL APPROACH Chronic alcoholic liver injury was induced by placing male C57BL/6 mice on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Human hepatic stellate cells line, LX-2 cells were pretreated with physcion for 1 h prior to ethanol stimulation. KEY RESULTS Physcion effectively ameliorated ALD-induced serum aminotransferase and triglyceride levels, steatosis, activated SIRT1-AMPK signaling, then inhibited hepatic NLRP3 inflammasome activation and GSDMD relevant in pyroptosis, the same as the hepato-protection of AMPK and SIRT1 agonists. Physcion suppressed ECM accumulation through inhibiting collagen-Ⅰ and α-SMA expression. Moreover, physcion prevented the accumulation of HMGB1 and NF-κB p65 nuclear translocation and release. Importantly, silencing of SIRT1-AMPK signaling eliminates the protective effect of physcion. CONCLUSIONS AND IMPLICATIONS Activation of SIRT1-AMPK signaling is involved in ALD pathogenesis, which alleviated by physcion through inhibiting NLRP3 inflammasome activation, inflammatory response and pyroptosis. Therefore, manipulation of hepatic inflammation and pyroptosis through strategies by targeting SIRT1-AMPK signaling holds great therapeutic potential for ALD.