Sepsis in humans is a difficult condition to treat and is often associated with a high mortality rate. Here, we investigated putative protective effects of Liu-Shen-Wan (LSW), a well-known Chinese formula used in treating infectious diseases, against polymicrobial sepsis induced by cecal ligation and puncture (CLP). The oral administration of LSW, at the first dose of 60 mg/kg and then 30 mg/kg every 12 h, significantly improved the survival of CLP mice during a 4-day observation period. The effects of LSW on the inflammatory response (circulating tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) levels and malondialdehyde (MDA) content—an index of lipid peroxidation), infectious degree (peritoneal bacteria counts), and innate immunity function (leukocyte counts, macrophage phagocytosis and neutrophil respiratory burst) were further examined in rats. We demonstrated that treatment of LSW significantly decreased elevated levels of circulating TNF-α at 4 h and further reduced plasma MDA levels at 24 h after CLP, at first doses of 15 and 30 mg/kg and then 7.5 and 15 mg/kg every 12 h. Moreover, LSW markedly enhanced clearance of intraperitoneal bacteria associated with the increasing count of peritoneal leukocytes and enhancing phagocytic activity of macrophages partly impaired at 24 h after CLP. In contrast, LSW lightly reduced IL-1 levels at 4 h and failed to improve deactivated respiratory burst activity of neutrophils at 24 h after CLP. Thus, LSW exerts protective effects against sepsis induced by CLP, mainly by reducing plasma TNF-α and MDA levels and enhancing peritoneal macrophage phagocytosis, suggesting that it is a potential agent in the prevention and treatment of sepsis.