The mouse model of ulcerative colitis was established with 5% sodium dextran sulfate to study the efficacy of Chinese yam peel polyphenols in preventing intestinal mucosal damage. Histopathological analysis, Western blotting and TUNEL staining were used to observe the disease activity index and the pathological changes of colon tissue in each group, and the relative expression of key proteins and the apoptosis rate of colonic epithelial cells were determined. The results showed that the disease activity index and the pathomorphology of colon tissue were significantly improved in mice treated with Chinese yam peel polyphenols. Chinese yam peel polyphenols also increased the expression of tight junction protein Occludin, prevented intestinal mucosal from the damage of mechanical barrier, reduced the expression of Caspase-8 and the apoptosis of colonic epithelial cells, and inhibited the expression of cyclooxygenase-2. Among them, the effect of oral administration of Chinese yam peel polyphenols with mass concentration of 240mg/(kg·d) was the best. Therefore, Chinese yam peel polyphenols could prevent intestinal mucosal injury in mice, and its molecular mechanism might be related to the inhibition of cyclooxygenase-2 expression.