Abstract: Objective To study the protective effect of isoflurane preconditioning on hepatic ischemia-reperfusion (I/R) injury mediated by the noncanonical pyroptosis pathway. Methods Thirty C57BL/6 mice were randomly divided into sham-operated group, isoflurane group and I/R group, and in the latter two groups, hepatic I/R injury was induced by clamping the portal vein for 30 min. In isoflurane group, the mice were pretreated with 1.4% isoflurane 30 min before the surgery. The protective effect of isoflurane preconditioning against hepatic I/R injury was evaluated by assessing the pathological score of HE staining of the liver tissue and serum ALT and AST levels. Serum IL-1β and IL-18 levels and the protein expression of GSDMS were detected by ELISA and Western blotting to evaluate the inhibitory effect of isoflurane preconditioning on pyroptosis. Western blotting and immunofluroescence were used to detect the protein expression of caspase-11 in the liver tissues to evaluate the inhibitory effect of isoflurane preconditioning on noncanonical pyroptosis pathway. Results The Suzuki’s score of the liver tissue was significantly higher in I/R group than in the sham group (P<0.05), while the score in the isoflurane group was significantly lower than that in the I/R group (P<0.05). Serum ALT and AST levels significantly increased in the sham group (P< 0.05), and were significantly lower in isoflurane group than in I/R group (P<0.05). The serum levels of IL-1β and IL-18 were significantly higher in I/R group than in sham group (P<0.05), and were significantly lower in isoflurane group than in I/R group (P<0.05). The expression of GSDMD in the I/R group was significantly higher than that in sham group, and was significantly lower in isoflurane group than in I/R group (P<0.05). The hepatic expression of caspase-11 was significantly higher in I/R group than in sham group (P<0.05), and was significantly lower in isoflurane group than in I/R group (P<0.05). Conclusion Isoflurane preconditioning has protective effect against hepatic I/R injury, which is related to the inhibition of the noncanonical pyroptosis pathway