This study aims to develop an optimized generic oral semaglutide formulation using the Design of Experiments (DoE) approach. Semaglutide is used to treat type 2 diabetes and also serves as an anti-obesity drug. Currently, Novo Nordisk has commercialized the oral formulation Rybelsus®. In this study, the DoE approach was employed to determine the optimal formulation that maintains appropriate tablet hardness while achieving a dissolution profile comparable to the reference drug in three dissolution medium. Minitab 21, a statistical software for experimental design, was used to set filler and binder as the input variables (X values). The filler concentration was designed within the range of 9–21%, while the binder concentration was set between 0–5%. Critical Quality Attributes (CQAs), including dissolution rate across three dissolution conditions and tablet hardness, were selected as response variables (Y values). The design space and response optimization tools identified an optimal formulation containing 15.9% filler and 3.5% binder, which exhibited a dissolution profile similar to the reference drug under all test conditions while maintaining appropriate tablet hardness. This study successfully optimized the formulation through a multivariate experimental approach, contrasting traditional single-variable methods. The application of DoE reduced time and costs, demonstrating its effectiveness in accelerating formulation development and enhancing process efficiency.