In this study, the synthetic process of 18α-glycyrrhizic acid was optimized. Using 18β-glycyrrhizic acid monoammonium salt as the starting material, the target compound 18α-glycyrrhizic acid was obtained through isomerization, esterification, and hydrolysis, with a total yield of 9.43%, purity of 99.23% and key impurity A of 0.17% (HPLC). The optimized process significantly improved the isomerization conversion rate, reduced the formation of related substances, simplified the purification steps, and enhanced both industrial scalability and cost efficiency.