Sepsis was characterized by systemic inflammatory response and multisystem organ dysfunction, refering to the activation of inflammatory and oxidative stress pathways. Estrogen has been shown to have anti-inflammatory and antioxidant effects as well as extensive organ protective role. However, whether estrogen alleviates sepsis-induced liver injury and the mechanisms involved remain unknown. Septic mice were constructed by intraperitoneal injection lipopolysaccharide, and the effect of estrogen on liver injury was investigated. Furthermore, the roles of NLRP3 inhibitor MCC950 and mitochondrial ROS specific scavenger Mito-tempo, on the liver injury were explored in septic mice. Female septic mice exhibited liver damage with increased serum AST and ALT level as well as the existence of extensive necrosis, and which was more serious in male septic mice. Moreover, Ovariectomy (OVX) aggravated sepsis-induced liver damage and activation of pyroptosis signaling pathway, which was alleviated by estrogen as evidenced by decreased serum AST, ALT level and number of infiltrating inflammatory cell, as well as protein expression related to pyroptosis. OVX aggravated mitochondrial dysfunction and liver injury in septic mice was also partly reversed by Mito-tempo and MCC950. These results demonstrated that estrogen protected against sepsis-induced liver damage through alteration of mitochondrial function and activation of inflammatory-mediated pyroptosis signaling pathway.