Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder often associated with obesity and elevated cardiovascular risks. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become integral to T2DM management due to their clinical benefits of glucose regulation and weight loss. However, their subcutaneous administration presents challenges to patient adherence, limiting their widespread use. Oral semaglutide (Rybelsus), the first oral GLP-1 RA approved for T2DM, addresses these challenges through an innovative co-formulation with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which enhances gastric absorption and stability. This review provides a comprehensive overview of the clinical development of oral semaglutide, with a focus on early-phase trials. Phase 1 studies investigated pharmacokinetics, pharmacodynamics, safety, and dose-response relationships, demonstrating a dose-dependent reduction in hemoglobin A(HbA) and body weight with an acceptable safety profile. Additionally, pharmacological evaluations of interactions with food, dosing condition, disease states, and concomitant medications supported the determination of an optimal dosing regimen for further clinical studies. Phase 2 dose-finding trials confirmed significant HbAand weight reductions comparable to subcutaneous semaglutide, which guided dose selection for phase 3 trials. Phase 3 trials, including the Peptide InnOvatioN for Early diabEtes tReatment program, demonstrated significant reductions in HbA, weight loss, and cardiovascular safety, positioning oral semaglutide as a transformative option in diabetes care. The study highlights comprehensive clinical strategies and provides an insight into the future development of oral GLP-1 RAs and other oral peptide drugs.