Ulcerative colitis (UC) is currently the most common inflammatory bowel disease (IBD). Due to its diverse and complex causes, there is no cure at present, and researchers are constantly exploring new therapies. In recent years, nano-selenium particle(SeNP) has attracted wide attention due to excellent biological activities. Therefore, in this study, for the first time, we used a natural polysaccharide,Eucommiaulmoides polysaccharide (EUP), modified SeNP to get EUP-SeNP with a size of about 170 nm, and its effect on 3% dextran sulphate sodium (DSS) induced colitis was explored. Our results showed that colon intestinal histology, intestinal mucosal barrier, inflammatory cytokines and intestinal microbiome composition were changed after EUP-SeNP treatment in colitis mice. Specifically, it was also shown that oral treatment of EUP-SeNP could relieve the degree of DSS-induced colitis in mice by restoring weight loss, reducing disease activity index (DAI), enhancing colon antioxidant capacity and regulating intestinal microbiome composition. In addition, we verified the mechanism in intestinal epithelial cell lines, showing that EUP-SeNP inhibited LPS-induced activation of the TRL-4/NF-κB signaling pathway in intestinal epithelial cell lines. To some extend, our study provides therapeutic reference for the treatment of IBD.