Hypomagnesemia is a significant risk factor for critically ill patients to develop sepsis， a life-threatening disease with a mortality rate over 25%. Our clinic data analysis showed that hypomagnesemia is associated with a decreased monocyte count in septic patients. At the cellular level， we found that Mg inhibits pyroptosis. Specifically， Mg limits the oligomerization and membrane localization of gasdermin D N-terminal (GSDMD-NT) upon the activation of either the canonical or noncanonical pyroptotic pathway. Mechanistically， we demonstrated that Ca influx is a prerequisite for the function of GSDMD-NT. Mg blocks Ca influx by inhibiting the ATP-gated Ca channel P2X7， thereby impeding the function of GSDMD-NT and inhibiting lipopolysaccharide (LPS)-induced noncanonical pyroptosis. Furthermore， Mg administration protects mice from LPS-induced lethal septic shock. Together， our data reveal the underlying mechanism of how Mg inhibits pyroptosis and suggest potential clinic applications of magnesium supplementation for sepsis prevention and treatment.