Objective To investigate the mechanism of pioglitazone (PIO) for preventing and treating non-alcoholic steatohepatitis (NASH) via observing the effect on the NLRP3 inflammsome signaling pathway in liver of mice with NASH. Methods Eighteen SPF healthy male C57BL/6J mice were randomly divided into control group, high fat diet (HFD) model group and PIO group. A HFD was given for 16 weeks to establish the NASH models, Then the PIO group was treated with PIO iva gavage for 6 weeks, and the control group and HFD model group were given normal saline as placebo. Serum levels of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT) and aspartic transaminase (AST) were detected, and liver histopathological changes were observed by HE and oil-red O staining. The mRNA expression of nucleotide binding oligomeric domain like receptor 3 (NLRP3) and apoptosis-associated speck-like protein (ASC) in liver tissues were detected by Realtime PCR. The protein levels of NLRP3, caspase-1 and interleukin-1β (IL-1β) in liver were detected by immunohistochemistry and Western blot.Results Compared with the normal control group, the serum levels of FBG, TC, TG, ALT and AST in the HFD model group were significantly elevated (all P＜0.05), and hepatic steatosis was more obvious. In addition, the mRNA expression levels of Nlrp3 and Asc in the liver tissues were significantly increased in the HFD model group, and the protein levels of NLRP3, caspase-1 and IL-1β were also increased (all P＜0.05). However, contrast to the HFD model group, pioglitazone treatment significantly decreased the serum levels of FBG, TC, TG, ALT and AST (all P＜0.05), improved hepatic lipid deposition, reduced the mRNA levels of Nlrp3 and Asc, and decreased the protein levels of NLRP3, caspase-1 and IL-1β in the liver tissues (all P＜0.05). Conclusion Pioglitazone can effectively reduce the liver inflammation in HFD-induced NASH mice, which may be associated with the inhibition of NLRP3 inflammasome activation and IL-1β production in the liver