Vonoprazan fumarate is a potassium-competitive acid blocker, and a rapid and robust chromatographic method is needed for its routine quality control. A reversed-phase HPLC (RP-HPLC) method was developed using an Analytical Quality by Design (AQbD) approach. Acetonitrile content, buffer pH and flow rate were studied using a 15-run design of experiments with retention time as the response, and the optimized method was validated according to ICH guidelines. Separation was achieved on an X-Bridge C18 column (2.1 × 100 mm, 3.5 µm) with phosphate buffer (pH 3.0) and acetonitrile (95:5, v/v) at 1.0 mL/min and 230 nm, giving a retention time of about 2.83 min. A quadratic model described the retention time data very well (R2 = 0.9999), and acetonitrile content had the strongest influence. The method was linear over 2–10 µg/mL (R2 = 0.9997), with a mean recovery of 99.97%, a system precision of 0.28% RSD, an LOD of 1.18 µg/mL, an LOQ of 3.58 µg/mL and robustness %RSD values below 2%. The assay of a tablet formulation was 99.93% of the label claim. The method is rapid, specific, accurate, precise and robust, and is suitable for routine quality control of vonoprazan fumarate. Forced degradation studies were not part of this work.