Sepsis, a common clinical complication, leads to multi-organ damage due to systemic infection and currently lacks effective therapeutic drugs. Polysaccharide derived from Tetrastigma hemsleyanum Diels et Gilg (TH), abbreviated as THP, is a water-soluble component extracted from TH, exhibiting anti-inflammatory and immunomodulatory properties. This study aims to investigate the effects and mechanisms of THP in sepsis. Results demonstrated that THP reduced neutrophils in the peripheral blood of mice established by cecal ligation and puncture (CLP), and inhibited IL-6 and MCP-1 in plasma, thereby improving systemic inflammation. THP ameliorated pulmonary edema, mitigated lung and liver histopathological injuries, reduced infiltration of neutrophils and macrophages in the lung and liver, and inhibited the TNF-α, IL-6, IL-1β, and MCP-1 transcription in both organs. Additionally, THP decreased myeloid cells, neutrophils, monocytes, and Tregs in the spleens of septic mice, while increasing T cells, CD4