Objective：To observe the effects of Caspase-1-mediated pyroptosis on neuronal injury in sepsis mice. Methods：Mouse model of sepsis was established by cecal ligation and puncture（CLP）surgery. Ninety adult male C57BL/6 mice were randomly divided into four groups：Sham+saline group（n=15，Sham group），Sham + Caspase-1 inhibitorAc-YVAD-CMKgroup（N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone，n=15，Sham+CMK group），CLP + saline group（n=30，CLP group）and CLP+Ac-YVAD-CMK group（n=30，CLP+CMK group）. Seven days after surgery，the brain of each mouse（n=6/each group）was rapidly harvested for determiningthescore of neuronal injury，number of Caspase-1-immunoreactive cells，contents of cleaved Caspase-1，pyroptosisbiomarker Gasdermin-D（GSDMD），interleukin-1β（IL-1β）and IL-18. Fourteen days after surgery，fear conditioning test was performed to evaluate the cognitive function for the rest of the mice. Results：Compared with the Sham group，the score of neuronal damage，number of Caspase-1-immunoreactive cells，contents of cleaved Caspase-1，GSDMD，IL-1β and IL-18 were significantly increased in the CLP group（P < 0.05），and mice of CLP group exhibited significant hippocampus-dependent cognitive impairment. Compared with the CLP group，increase of Caspase-1，GSDMD，IL-1β and IL-1β were inhibited by Ac-YVAD-CMK administration in the CLP+CMK group（P < 0.05）. Conclusion：Sepsis induces neuronal injury and activation of Caspase-1-mediated pyroptosis in mice hippocampus，and inhibiting Caspase-1 with Ac-YVAD-CMK ameliorates sepsis-induced pyroptosis，neuronal injury and cognitive impairment.