Cisplatin is a commonly used drug against solid tumors. However, it can cause cell death in rapidly dividing intestinal epithelial cells. Enteromorpha (EP), an edible marine alga found in eastern China, and its polysaccharide fraction (PEP), can relieve constipation and modulate the intestinal microbiota. The aim of our study was to investigate the possible role of PEP in preventing cisplatin induced intestinal damage and gut microbiota imbalance in a mouse model. Cisplatin disturbed the intestinal microbiota and damaged the intestinal barriers. PEP treatment prior to cisplatin injection ameliorated these injuries and restored the gut microbial composition. We also analyzed the diversity of the fecal bacterial population by 16S DNA sequencing, and found a high abundance of the Escherichia – Shigella genera in the cisplatin treated mice. In conclusion, our results indicate that PEP is a powerful natural product that can protect against the gastrointestinal side effects of cisplatin.