Lyophyllum decastes has been used for culinary purpose. The present study was conducted to evaluate the antioxidant and anti-inflammatory effects from methanol, acetone, and hot water extracts of L. decastes fruiting bodies. The acetone and methanol extracts showed the higher 1,1-diphenyl-2-picryl-hydrazy radical scavenging activities than that of the hot water extract at 0.5–2.0 mg/mL and was comparable to the BHT, the positive control. The ferrous ion chelating effects of the mushroom extracts at 0.5–2.0 mg/mL were significantly higher than that of BHT. The reducing power of acetone extract (2.12) was significantly lower than that of BHT (2.73) at 2.0 mg/ mL. The mushroom extracts also showed inhibitory effects on production of nitric oxide (NO), and expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide-induced murine macrophage cells in a concentration dependent manner. In vivo anti-inflammatory experiment on carrageenan-induced hind-paw edema of rat model, the acetone extract of the mushroom significantly suppressed the carrageenan-induced rat hind paw edema of rats in a dose dependently. The results suggest that the fruiting bodies of Lyophyllum decastes are a good natural resource of antioxidant and anti-inflammation.