Fucoidan is a popular polysaccharide known to have important biological functions. In the present research, the therapeutic effect of fucoidan on gastrointestinal illness induced by lipopolysaccharide (LPS) in mice was determined. A total of thirty ICR mice were divided into three groups, including group C, M and Y. Mice in group Y were treated with fucoidan (200 mg/kg b.w.) for 14 days, while mice in groups C and M received normal saline. On day 15, the mice in group M and Y were challenged with LPS @10mg/kg b.w. by intra-peritoneal injection. After 24 hours, the mice in all groups were euthanized and different samples were collected for analysis. Results showed that fucoidan decreased the weight loss in mice to a certain degree and alleviated the intestinal damage caused by LPS by improving ratio of villus length/crypt depth, through increasing villus length and decreasing crypt depth in mice. It was established that mice treated with fucoidan had a significantly higher levels of T-AOC (P<0.01), GSH-Px (P<0.001), IL-10 (P<0.001) and SOD (P<0.01) and a significantly lower levels of MDA (P<0.001) and TNF-α (P<0.05), indicating that fuciodan may have protective effect against oxidative damage by LPS. Microbiota analysis revealed that the number and abundance of phyla and genera found in the microbiome of mice in group Y were close to those of mice in group C, indicating that fucoidan may promote the biodiversity of microbiota in mice. Taken together, the fucoidan may have protective effect against intestinal damages in mice by regulating oxidation resistance, inflammatory response and improving microbiota.