Aim <p>This study aimed to develop and validate a chromatography-based analytical method for the quantification of Vonoprazan fumarate in pharmaceutical formulations, minimizing solvent consumption. A single chromatographic condition was optimized using the principles of design of experiments (DoE) and an analytical quality by design (QbD) approach, in compliance with regulatory guidelines.</p> Methods <p>The method was validated per ICH guidelines, assessing linearity, system suitability, accuracy, precision, robustness, specificity, solution stability, and filter compatibility. Box–Behnken response surface methodology was employed to optimize critical method parameters (CMPs) based on the analytical target profile. Green analytical tools, including the Green Analytical Procedure Index (GAPI), National Environmental Method Index (NEMI), Analytical GREEnness Metric (AGREE), and Analytical Eco-Scale (AES), were applied to evaluate environmental impact.</p> Results <p>The method exhibited excellent linearity (<i>R</i>² = 0.9999) within a working concentration range of 7.5–22.5&#xa0;µg&#xa0;mL⁻¹. Recovery studies at 50–150% concentrations demonstrated 99–101% accuracy. The assay of Vonoprazan yielded 100.6%, with a retention time of 1.825&#xa0;min. Intra- and inter-day precision showed relative standard deviations below 2%. Robustness studies confirmed method stability under varied conditions. The Box–Behnken design demonstrated a significant quadratic relationship between CMPs and critical material attributes (CMAs).</p> Conclusion <p>The developed HPLC method provides accurate, precise, and specific quantification of Vonoprazan in bulk and formulations. Its excellent recovery, minimal standard deviation, and eco-friendly profile make it suitable for routine pharmaceutical analysis, confirming its reliability and sustainability.</p> Graphical Abstract <p></p>