Inflammatory bowel disease (IBD) is a prevalent condition worldwide, characterized by complex etiologies, limited efficacy of clinical drug treatments, and potential adverse effects. In this study, we designed 269 nm selenium nanoparticles with double-cell targeting for ulcerative colitis treatment. Somatostatin (SST) and mannooligosaccharide (MOS) were employed to functionalize an Eucommia ulmoides polysaccharide selenium nanoparticle (EUP-SeNP), resulting in the formulation of SST/MOS@EUP-SeNP. Nanoparticles were engineered to target intestinal epithelial cells and macrophages through specific cell surface receptors, enabling dual-targeted treatment. In addition, sodium alginate (SA) microspheres incorporating SST/MOS@EUP-SeNP were prepared for oral administration, protecting the nanoparticles from gastric fluid. The results showed that SA/SST/MOS@EUP-SeNP could preferentially target the inflamed colon tissue and adhere to the colon, enhance the intestinal barrier function, regulate the level of colon inflammation, enhance antioxidant capacity, and regulate the composition of intestinal microbes to effectively relieve the colitis induced by sodium glucan sulfate (DSS). Meanwhile, SA/SST/MOS@EUP-SeNP had excellent biocompatibility both in vivo and in vitro. To some extent, this study can provide a reference for the treatment of IBD.