The dry-cured hams are produced by a long-term fermentation along with amounts of bioactive peptides are generated. Previously, the bioactive peptides in ham have been reported with antioxidant, antihypertensive, and anti-inflammatory effects. Currently, the Xuanwei ham peptides (XP) were evaluated in dextran sodium sulfate (DSS)-induced C57BL/6 mice trial to investigate their effects on inflammatory bowel disease (IBD) symptoms. As result, the IBD symptoms of colon shorten, tissue damage, and colonic tissue inflammation were all ameliorated in the supplement of XP. The inflammatory cytokines (TNF-alpha, IL-6, MCP-1) in the colon were also suppressed by XP intervention compared to DSS-induced treatment. In addition, the intake of XP was checked to modulate the gut microbiota structure, including increasing the relative abundances of Akkermansia, Parasutterella, Dorea, and decreasing the relative abundances of Saccharibacteria, Olsenella, Peptococcus. Generally, the results implied that XP could attenuate the DSS-induced colitis symptoms by regulating the secretion of inflammatory cytokines as well as regulating the gut microbiota.