The present work aimed to investigate the antioxidation, hepatic- and renal-protection of water-extractable polysaccharides (WPS) by Dictyophora indusiata fruiting body on high-fat emulsion-induced obese mice. The structural analysis indicated that WPS was the α-configurational heteropolysaccharide with the major monosaccharides of mannose and glucose, and the polydispersity of 1.77. The in vivo results showed that WPS administration could improve obesity-associated hepatic and renal metabolic impairment, reduce body weight and ameliorate oxidative stress of liver and kidney by down-regulating serum enzyme activities and hepatic lipid levels, stabilizing serum lipid status, enhancing antioxidant abilities and decreasing insulin and leptin resistance. The in vitro experiments showed that WPS had potential abilities to scavenge free radicals. The conclusions demonstrated that WPS might be used as a salutary food and natural medicine for preventing obesity-associated damage and its complications.