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1,25-Dihydroxyvitamin D [1,25(OH)₂D₃] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)₂D₃ protects patients from sepsis, but clinical treatment with 1,25(OH)₂D₃ is rare. In this study, we report that 1,25(OH)₂D₃ treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)₂D₃via blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)₂D₃ can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)₂D₃ on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)₂D₃ upon LPS exposure. Together, we provide evidence that 1,25(OH)₂D₃ attenuates LPS-induced HMGB1 secretion via the Nrf2/HO-1 pathway in macrophages.