Background and Purpose: Regulating P2X7 receptor‐mediated activation of NLRP3 inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process was modulated by gentiopicroside, the main active secoiridoid glycoside from Gentiana manshurica Kitagawa.Experimental Approach: In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administered ethanol or using chronic plus binge ethanol feeding of Lieber‐DeCarli liquid diet to male C57BL/6 mice. In vitro, HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone marrow‐derived macrophages (BMDMs) were stimulated with LPS and ATP.Key Results: In both the acute and chronic alcohol‐induced mouse hepatosteatosis models, gentiopicroside decreased serum aminotransferases and triglyceride accumulation. Up‐regulated SREBP1, down‐regulated PPARα and phosphorylated acetyl‐CoA carboxylase caused by acute and chronic alcohol feeding were modulated by gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 receptor‐NLRP3 activation by gentiopicroside inhibited IL‐1β production. In ethanol‐exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted lipid oxidation via activation of P2X7 receptor‐NLRP3 inflammasomes. Genetic or pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced SREBP1 expression in ethanol‐treated HepG2 cells. Gentiopicroside down‐regulated P2X7 receptor‐mediated inflammatory responses in LPS/ATP‐stimulated RAW 264.7 macrophages and BMDMs. IL‐1β from macrophages accelerated lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by gentiopicroside.Conclusions and Implications: Activation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor‐NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.