Sepsis is a high-mortality disease in which dysregulated production of pro-inflammatory cytokines cause multi-organ defects and lead to endotoxic shock. Despite the extensive use of anti-inflammatory treatments (e.g. TNF-α antibody or glucocorticoids) in patients undergoing endotoxic shock, its mortality rates remain high at approx.30%, indicating that the mechanism of endotoxic death is only partially explained by uncontrolled inflammation. In this study, we identified an anti-microbial peptide, Reg3γ, as a protective factor against endotoxic death. During endotoxemia, nociceptor-derived Reg3γ penetrates into the brain and suppresses the kynurenine pathway. Endotoxin-administered nociceptor-null mice and nociceptor-specific Reg3γ-deficient mice exhibit a high mortality rate accompanied by an aberrant level of quinolinic acid and a decreased ATP production in the brain despite normal peripheral inflammation. Strikingly, the central administration of Reg3γ protects mice from endotoxic death. These findings provide novel insights into the molecular machinery of tolerance to endotoxic death.