Analytical quality by design (AQbD) and method orthogonality are comprehensive tools used to develop an analytical method based on statistical and graphical evaluation. These tools provide complete knowledge of the method and help to develop precise, accurate, and specific methods. The present work elaborates the development of a selective and precise method for the quantification of bosentan and its nine impurities with a short runtime of 10 min using a statistically driven stage-wise AQbD approach with proven orthogonality. The optimum method was developed using 10 mM ammonium acetate pH 2.5 and acetonitrile in a gradient mode on an Agilent Zorbax Bonus RP RRHD 100 × 2.1 mm and 1.8 μm column with a flow rate of 0.45 mL/min at a column temperature of 40 °C. The robustness of the method was proven for the normal operating range (NOR) using Monte Carlo stimulations. The method was challenged using an orthogonal method that was developed based on the trellis graphs and surface response outcome of the design of experiment (DoE). The orthogonality factor between methods was calculated by measuring the correlation coefficient (r) of the retention factor (k') calculated for each peak on both methods. A forced degradation study was performed to challenge the method, and stressed samples were analyzed using both orthogonal methods. The outcome of the experiment proved that the approach of developing methods using the AQbD approach and then challenging them with orthogonality helps to develop a robust method. The method was further validated as per ICH guidelines.