This study focused on optimizing sago-starch-derived sodium starch glycolate (SSG) as a superdisintegrant using a Response Surface Methodology (RSM). The aim was to enhance the formulation performance by achieving an optimal degree of substitution (DS) in the synthesis of SSG from sago starch and evaluating its performance in mefenamic acid tablet formulation. The SSG was synthesized using an organic solvent slurry method, which involves crosslinking starch with sodium trimetaphosphate (STMP) and substituting it with sodium monochloroacetate (SMCA). The reaction conditions, including the temperature, SMCA ratio, and reaction time, were optimized using the RSM. The optimal conditions were identified as a temperature range of 45–55 °C, an SMCA ratio of 0.75–1.5, and a reaction time of 120–240 min. The maximum predicted DS value was 0.24, with a validated DS value of 0.246 ± 0.021. The SSG-containing mefenamic acid formulation met USP standards and showed a superior disintegration time compared to the existing SSG. The optimized SSG derived from sago starch can be effectively used as a superdisintegrant in pharmaceutical formulations, offering a sustainable and economically viable alternative source of SSG. This contributes to the development of more effective drug delivery systems and promotes sustainable agriculture in Indonesia.