Background: Cognitive dysfunction after sepsis is the most serious complication after discharge of sepsis patients, and its pathogenesis is related to the inflammation of the central nervous system caused by the damaged blood-brain barrier. Interleukin-1β (IL-1β) is a key factor in sepsis-induced cognitive dysfunction in mice. Several investigations have suggested that TRPM2 (transient receptor potential melastatin-2) performs a vital task in immune response and inflammation. The aim of this exploration was to discover the importance of IL-1β in apoptosis in the hippocampal astrocytes of septic mice through in vitro and in vivo assessments. Methods: mouse severe inflammatory was established by intraperitoneal injection of high dose lipopolysaccharide (LPS, 5 mg kg–1), The Morris water maze task and fear conditioning test were used to investigate cognitive functions on the 7th day after LPS injection. Western blotting was implemented to detect the levels of IL-1β , TRPM2 and GFAP. Flow cytometry was employed to ascertain the effects of IL-1β and TRPM2-siRNA on the apoptosis of astrocytes. Immunofluorescent staining was used to examine the expression levels of GFAP and TRPM2 in hippocampus of mice .Results: Intraperitoneal injection of LPS caused cognitive dysfunction in mice, which can be reversed by down-regulation of IL-1β expression in the hippocampus. Elevated expression of IL-1β and TRPM2 were observed in hippocampus from the mouse after LPS injection. Specifc knockdown of IL-1β mRNA expression rescued the elevated expression of TRPM2. Accordingly, specifc knockdown of TRPM2 expression improved the cognitive impairment induced by Intraperitoneal injection of LPS.Conclusions: Elevated expression of IL-1β in the hippocampus may induce cognitive dysfunction by upregulation of TRPM2 in septic mice astrocytes.