Selenium-binding protein 1 (SELENBP1) has been implicated in cancer development, neurological disorders, tissue injury, metabolic regulation, and cell differentiation. Sepsis is characterized prominently by immunological dysregulation and severe organ damage. However, whether SELENBP1 improves sepsis by regulating immune cell activity remains unknown. Here, we detected an elevation of SELENBP1 levels in the blood of sepsis patients and in the livers of septic mice. Significantly, SELENBP1 knockout (KO) prolonged survival in septic mice. This phenomenon was accompanied by decreased liver damage, reduced inflammation levels, and an increased regulatory T cell/T helper 17 cell (Treg/Th17) ratio in the spleen. Additionally, SELENBP1 deficiency induced a redox imbalance and inhibited dendritic cell (DC) maturation, resulting in a tolerogenic DC (tolDC) phenotype and an increase in the Treg/Th17 ratio. Furthermore, SELENBP1-KO mature DCs (mDCs) alleviated liver injury by increasing the Treg/Th17 ratio in the spleen, thus improving the survival of septic mice. These findings indicate that SELENBP1 is involved in sepsis by regulating DC immune activity, which might provide a potential way for sepsis treatment.