Objective:To investigate the protective effect of Momordica charantia polysaccharide (MCP) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and the possible mechanism. Methods:MCP was extracted from Momordica charantia (MC). Fifteen C57BL/6J mice were randomly divided into three groups with five in each group: control group, DSS group and DSS+ MCP group. The body weight and disease activity index (DAI) of the mice were monitored every day. Mouse colon tissues and serum samples were collected. Pathological changes in intestinal tissues and the expression of inflammatory factors, CD4 + T cells, neutrophils and macrophages were analyzed by HE staining, ELISA, RT-qPCR and flow cytometry. Results:MCP alleviated the DSS-induced UC in mice by restoring body weight and stool consistency and reducing bleeding. Moreover, MCP could repair the mucosal barrier function of colon tissues, decreasing inflammatory cell infiltration and lessening the edema in mucosal layer and muscle layer, and therefore protect the damaged intestinal tract of mice. The expression of inflammatory cytokines (TNF-α and IL-1β) and the level of CD4 + T cells were decreased in the colonic tissues of MCP-treated mice. Conclusions:MCP ameliorated DSS-induced UC in mice through inhibiting weight loss, repairing colonic tissue damage, improving immune system disorder and decreasing the expression of inflammatory cytokines. This study provided reference for further study of MCP as a potential dietary intervention in the treatment of UC.