In this work, the effects of sulfated polysaccharides from Lentinula edodes (SPLE) on zymosan (ZYM)-induced multiple organ dysfunction syndrome (MODS) mice were investigated. Using the MODS mice model, biochemical works have already shown that in mice treated with SPLE, the lung parameters of GGT, C3 and hs-CRP were down-regulated and the hepatic parameters of TC, TG, ALT and AST, HDLC, LDL-C and VLDL-C were improved, the serum levels of CK, Cr and Amy were decreased, and the levels of inflammatory factors such as TNF-α, IL-1β, IL-6 and IL-10 were also reduced, the activity of antioxidant enzymes SOD and CAT enhanced, and the content of MDA was reduced. In addition, histopathology of the lung and liver confirmed the beneficial effects of SPLE on MODS mice, indicating that SPLE played a role in protecting the organ function of MODS mice. In addition, SPLE was characterized as a sulfated β-glucan linked by β-type glycosidic bonds. These conclusions indicated that SPLE had effective antioxidant and anti-inflammatory activities, and could be used as a functional food and medicine to prevent MODS.