Purpose <p>To develop and validate a robust, precise, and stability-indicating RP-HPLC method for the quantitative estimation of topiramate in nanocochleate formulations using an Analytical Quality by Design (AQbD) approach, ensuring reliable analysis despite formulation complexity and degradation susceptibility.</p> Methods <p>A systematic AQbD framework was employed to identify and optimize critical method parameters through risk assessment. A Box–Behnken design coupled with response surface methodology was used for optimization. Chromatographic separation was achieved on a C18 column using a mobile phase of acetonitrile and 0.1% formic acid (70:30, v/v) at an optimized flow rate, with detection at 263&#xa0;nm. The method was validated as per ICH Q2(R1) guidelines. Forced degradation studies were conducted under acidic, alkaline, oxidative, thermal and photolytic conditions. Greenness of the method was also evaluated using standard analytical assessment tools.</p> Results <p>The method showed excellent linearity over the concentration range of 2–12&#xa0;µg/mL with a correlation coefficient (R²) greater than 0.999. It demonstrated high precision, accuracy, and sensitivity. Degradation products were well-resolved from the main drug peak, confirming its stability-indicating capability. The method was successfully applied to nanocochleate formulations, yielding high recovery with no significant interference from excipients. Additionally, greenness evaluation confirmed the environmentally friendly nature of the method.</p> Conclusion <p>The developed RP-HPLC method is reliable, reproducible, and stability-indicating, making it suitable for routine quality control, stability testing, and quantitative analysis of topiramate in complex nanocochleate drug delivery systems.</p> Graphical Abstract <p></p>