Ulcerative colitis (UC) is characterized by chronic relapsing and persistent inflammation that mainly affects the colon. The purpose of this study was to investigate the therapeutic effect of Agaricus blazei Murrill polysaccharides (ABP) or selenium-enriched Agaricus blazei Murrill polysaccharides (ABP-Se) on UC. UC mouse model was established by 2.5% dextran sulfate sodium (DSS). Markers for colonic barrier functions, cytokines and oxidative stress were measured. The experimental results showed that ABP and ABP-Se significantly alleviated UC-related symptoms, including weight loss, colon shorten, and disease activity index scores. Meanwhile, ABP and ABP-Se significantly promoted tight junction proteins and mucus content, and decreased inflammation and oxidative stress. Moreover, ABP-Se exhibited a better anti-oxidative ability compared to ABP. The experimental results suggest that ABP and ABP-Se relieve DSS-induced colitis via reducing inflammatory cytokines and oxidative stress, and preventing colonic barrier damage. This study suggests a promising therapeutic effect of mushrooms-derived polysaccharides on UC.