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BACKGROUND: Sanghuang mushrooms are medicinal fungi widely used in eastern Asia. In this study, the antioxidant and anti‐inflammatory activity of a novel extracellular polysaccharopeptide, sanghuang extracellular polysaccharopeptide (SePSP) was investigated. The SePSP was purified from the submerged fermentation broth of a sanghuang mycelium, Sanghuangporus lonicericola strain CBS17, which was isolated from a wild sanghuang fruiting body. RESULTS: The SePSP was extracted using an ethanol precipitation procedure, followed by diethylaminoethanol (DEAE) anion‐exchange and size‐exclusion chromatography. The mass ratio of the polysaccharide and peptide components in the purified SePSP was approximately 4.87:1. By determining its free radical scavenging abilities using 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), the hydroxyl free radical, and the superoxide anion free radical, as well as its total reducing power, SePSP was shown to have strong concentration‐dependent antioxidant activity in vitro. Further, SePSP effectively alleviated dextran sodium sulfate (DSS)‐induced ulcerative colitis (UC) in mice. Administration of 200 mg kg−1 SePSP by gavage for 7 days prevented body weight loss; significantly reduced the mRNA levels of proinflammatory cytokines, including TNF‐α and IL‐1β; increased mRNA level of the anti‐inflammatory cytokine IL‐10 in the colon, and decreased the malondialdehyde concentration from 6.42 to 4.82 μmol L−1 in the blood in UC mice. CONCLUSION: The SePSP had strong concentration‐dependent antioxidant activity in vitro and effectively alleviated DSS‐induced UC in mice. The in vivo therapeutic efficacy in DSS‐induced UC may be mediated by modulating the expression of inflammatory cytokines and inhibiting oxidative stress. The findings provide a scientific rationale for the use of bioactive nutraceuticals from sanghuang mushrooms to develop functional foods for the prevention and treatment of UC. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]