Abstract Development and optimization of analytical methods for quantifying verapamil hydrochloride in its twelve impurities is a challenge for analytical chemists and pharmacists. The aim of this paper was to apply the analytical quality by design (AQbD) and design of experiments (DoE) approaches in the development of a robust, low-cost, regulatory-flexible, fit for purpose high-performance liquid chromatography (HPLC) analytical method to determine VPM and its impurities. A Placket-Burman screening design was adopted to identify the most relevant analytical conditions affecting the chromatographic responses. In addition, a central composite optimization design was used to establish regression models explaining the chromatographic responses as functions of the buffer pH, concentration of ammonium hydroxide in mobile phase, and the injection volume of test solutions. Response surface methodology allowed for establishing the method operable design space, which ensures suitable method performance with respect to all chromatographic responses studied. Optimal chromatographic conditions were achieved using a gradient elution consisting of a mixture of 10 mM ammonium formate buffer pH and acetonitrile, with a flow rate of 0.7 mL/min, and a XSelect CSH C18 100 mm x 4.6 mm 3.5 µm chromatographic column. The optimized analytical method was selective, linear (320–480 µg/mL for VPM and 0.4–4.8 µg/mL for impurities), precise (0.5% and 1.0% for VPM and impurities, respectively), accurate (mean recovery of 101.0% and 102.5% for VPM and impurities, respectively), and robust. In addition, the application of the validated analytical method in forced degradation conditions allowed for studying the degradation profile of verapamil hydrochloride, particularly in acid and oxidative degradation conditions.