Abstract: Objective : To explore the effect of Houttuynia cordata polysaccharide (HCP) on dextran sulfate sodium salt (DSS) induced ulcerative colitis (UC) and its possible mechanism in mice. Methods : Fifty KM male mice were randomly divided into 5 groups (n=10): normal control group, model group, HCP low dose group (1 g/kg/day), HCP high dose group (2 g/kg/day), and Sulfasalazine positive group (SASP, 9 mg/kg/d). The UC model was induced with 2.5% DSS by water drinking for 9 days in mice. After successfully established the model in mice, the normal control group and the model group were free drinking distilled water, HCP in doses of 1 g/kg/day and 2 g/kg/day groups were given by filling to the stomach after DSS administration, and the positive group was treated with 9 mg/kg/d Sulfasalazine aqueous solution for 6 days. Assessing disease activity index (DAI) of mice in each group, observing colonic tissue structure by HE, detecting pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), leukocyte-mediated interleukin-1β (IL-1β) and interleukin-6 (IL-6) contents and detecting the liver and kidney biochemical indexs levels alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CR) and blood urea nitrogen (BUN) in serum by ELISA method, using 16S rRNA phylogenetic sequencing to detect the changes of intestinal flora in rat feces. Results : Compared with the model group, the DAI scores in both dosages of HCP were significantly decreased (P<0.05), the colonic tissue structures were dose-dependently improved. Also, HCP dose-dependently decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ) and the contents of liver and kidney biochemical indexs (ALT, AST, CR, BUN). In addition, the gut microbiota imbalance was modulated in HCP treated groups during colitis by increasing the gut microbial diversity. Conclusion : HCP may alleviate the symptoms of ulcerative colitis by improving the intestinal mucosal environment, reducing the level of inflammatory factors and maintaining the homeostasis of intestinal flora in mice.