Background: The study aims to integrate the Experiment Planning (DOE) methodologies with High-Performance Liquid Chromatography in the Reverse Phase (RP-HPLC) for the development of an analytical method to estimate lobeglitazone. Methods: A DOE strategy was applied to maximize critical method parameters for RP-HPLC, including mobile phase composition, flow rate, and column temperature. The method development was carried out using an analytical column Inspire with a C18 (150 × 4.6 mm,5 µm). stationary phase and acetonitrile containing mobile phase and potassium dihydrogen phosphate the procedure showed exceptional linearity range at wavelength of 240nm with a correlation coefficient (R²) of 0.999. The method was validated according to ICH guidelines, showing satisfactory results in terms of specificity, sensitivity, repeatability, and robustness. Results: The enhanced RP-HPLC technique demonstrated high precision and accuracy in the estimation of lobeglitazone. The DOE approach enabled systematic optimization, resulting in a robust method with improved sensitivity and reduced analysis time. Conclusion: The integration of with DOE in RP-HPLC method development offers a strategic approach to enhance analytical method performance. This study successfully established a reliable and efficient RP-HPLC technique for determining lobeglitazone, which can be potentially applied in quality control and pharmacokinetic studies.