Background: In hospitalized patients, drug side effects usually trigger off intestinal mucositis(IM), which in turn abates intestinal absorption and reduces the efficacy of treatment. It has been discovered that natural polysaccharides can relieve intestinal mucositis. In this study, we extracted and purified a homogenous polysaccharide of Wuguchong(HPW),one of traditional Chinese medicine, and explored the protective effect of HPW on 5-fluorouracil-induced IM. Methods and Results: Firstly, we identified the physical and chemical properties of the extracted homogeneous polysaccharides. The molecular weight of HPW was 616 kDa, which was composed of 14 monosaccharides. Then, a model of small intestinal mucositis induced by 5-FU (50 mg/kg) was constructed in mice to explore the effect and mechanism of HPW. The results showed that HPW effectively increased histological indicators such as villus height,crypt depth and goblet cell count. Meanwhile, it relieved intestinal barrier indicators such as D-LAC and DAO. Subsequently, western blot was used to detect the expression of Claudin-1, Occludin, PCNA, and inflammatory proteins such as NF-κB(P65), TNF-α, and COX-2. The figures also indicated that HPW could reduce inflammation and protect the barrier at the molecular level. Finally, we also investigated the influence of HPW on the content of SCFAs in feces of mice, a metabolite of intestinal flora. Conclusions: HPW, as a bioactive polysaccharide derived from insects, has protective effects on intestinal mucosa and can relieve intestinal inflammation caused by drug side effects, which deserves further development and research.