Diabetes is now a global chronic disease, with the number of people with diabetes expected to reach 643 million by the end of 2030. Semaglutide, a human glucagon-like peptide-1 (GLP-1) analogue with 94% similarity to human GLP-1, can promote insulin secretion and repress glucagon secretion in a glucose concentration-dependent manner, resulting in substantial improvement of blood glucose levels and reducing the risk of hypoglycemia in patients with type 2 diabetes. To improve the absorption efficiency of semaglutide in oral delivery, we developed chitosan hydrochloride-coated and nonionic surfactant-modified niosomes (CS.HCL-NSPEs-NIO) as a new way to encapsulate it. The results showed that CS.HCL-NSPEs-NIO could efficiently penetrate the cell junctions in the intestinal endothelium and therefore promote drug absorbance. In addition, gastrointestinal distribution studies revealed that CS. HCL-NSPEs-NIO could stay in the intestine for more than 4 h, thus allowing for long-term glucose regulation. Effective reduction of blood glucose levels and weight loss were observed in db/db mice while no toxicity was detected in major organs. On the whole, our recommendation is that CS.HCL-NSPEs-NIO shows promise as an oral delivery tool for enhancing the hypoglycemic effects of semaglutide.