A simple, sensitive, accurate and precise UPLC method was developed and used to validate simultaneously the mixture of Bilastine and Montelukast. The experimental design approach can be useful to optimize the separation and to help out in the development and better understanding of the interaction of several chromatographic factors on separation quality. Methods: A CCD design was employed to locate the optimum organic solvent volume, flow rate and pH for separation by mapping the chromatographic response surface. The qualities of the fitted polynomial models were examined on the basis of the coefficient of determination of R2 value. The true optimum condition position was recognized by employing Derringer’s desirability function, where responses were simultaneously optimized. The final step was to predict the response and design space from the polynomial equation. Results: As a result of using C18 the optimum chromatographic conditions, a high-quality resolution response appears. Percent recoveries were found to be close to 100% with low variability. Conclusion: The optimized assay condition was validated according to ICH guidelines to confirm specificity, linearity, accuracy and precision. The method possibly will be adopted for routine analysis in industry