AIMS: Nearly 48 million people have sepsis every year, and 11 million lose their lives as a direct consequence of the disease. In addition, sepsis is still the fifth leading death cause globally. The objective of this research was to find out whether pretreatment with Clemastine (CLM) would prevent septic liver damage. MAIN METHODS: Sepsis induction was established via CLP in male Wister rats. Histopathological analysis and hepatic function panel were assessed. The colorimetric method was used to assess hepatic contents of MDA, GSH, and SOD. ELISA was utilized to evaluate the hepatic TNF-α, IL-18, and IL-1β. qRT-PCR was utilized to evaluate caspase-3, Bax, Bcl-2, and NF-kB mRNA levels. Western blotting assessed NLRP-3, caspase-1, and GSDMD c-NT proteins. KEY FINDINGS: CLP induced hepatic dysfunction, ALT and AST elevation, increased oxidative stress parameters, and escalated hepatic levels of TNF-α, IL-18, and IL-1β. It also augmented NLRP-3, caspase-1, and GSDMD c-NT protein levels, elevated Bax, NF-κB, and caspase-3 mRNA levels, and concurrently inhibited Bcl-2 mRNA levels. Conversely, CLM significantly mitigated molecular, biochemical, and histological changes induced by sepsis. CLM decreased proinflammatory signals, suppressed the production of NLRP-3, caspase-1, and GSDMD c-NT proteins, repressed caspase-3, Bax, and NF-κB, mRNA expression, and enhanced Bcl-2 mRNA expression. SIGNIFICANCE: Finally, by suppressing the NLRP-3/Caspase-1 mediated pyroptotic cell death in rats, CLM pretreatment provided protection against septic-liver damage.