Sea cucumber, possessing various active compounds, is a traditional food in Asia. Acaudina molpadioidea is a kind of sea cucumber widespread in Eastern Asia. Sepsis is the systemic inflammatory response to infection predominantly from gram-negative bacteria. Here, we investigated the effect of active compounds of sea cucumber (A. molpadioidea) on the sepsis. Our results found the polysaccharides, but not polypeptides, from sea cucumber improved the survival in CLP induced septic mice. After polysaccharides oral administration, the colony-forming units (CFU) were all decreased in liver, spleen, and blood samples of septic mice compared with controls. The pro-inflammatory factors, IL-1 beta and TNF alpha, were both down regulated in the plasma of polysaccharides fed mice. There were similar plasma levels of IL-10 in polysaccharides and saline fed mice. The peritoneal macrophages from polysaccharides fed mice exhibited stronger phagocytosis and bacterial killing capabilities than controls. This study provides a kind of new potential food to possibly improve sepsis-related mortality in human.