In this study, we investigated the role of the non-canonical pyroptosis pathway in the progression of lethal sepsis. Our findings emphasize the significance of non-canonical pyroptosis in monocytes/macrophages for the survival of septic mice. We observed that inhibiting pyroptosis alone significantly improved the survival rate of septic mice, and the HMGB1 A box effectively suppressed this non-canonical pyroptosis, thereby enhancing the survival of septic mice. Additionally, our cell in vitro experiments further unveil that frHMGB1, originating from LPS-carrying histiocytes, enters macrophages via RAGE, resulting in the direct activation of caspase-11 and the induction of non-canonical pyroptosis. Notably, the A Box's competitive binding with LPS thereby impedes its entry into the cell cytosol. These findings reveal potential therapeutic strategies for slowing the progression of lethal sepsis by modulating the non-canonical pyroptosis pathway.