Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, coagulopathy and lethality in endoxemia and bacterial sepsis. The activation of caspase-11 requires high mobility group box 1 (HMGB1)-mediated translocation of LPS from the extracellular space to the cytosol. Here we show that HMGB1-dependent cytosolic delivery of LPS was blocked by glycyrrhizin, a medication to treat liver diseases. Glycyrrhizin competitively bound HMGB1 and thereby inhibiting the physical interaction between HMGB1 and LPS. Treatment of glycyrrhizin significantly attenuated caspase-11-dependent immune responses, coagulopathy, organ injury and lethality in endotoxemia and experimental sepsis. Together, our data suggest that pharmacological inhibition of the cytosolic delivery of LPS by glycyrrhizin might be a potential therapeutic strategy to treat sepsis, which is a leading cause of death in hospitals worldwide.