This research deals with optimization using the Derringer’s desirability function for the development of LCMS method for the estimation of three combination of drugs Telmisartan, Chlorthalidone and Metoprolol succinate in commercial pharmaceutical preparations used as antihypertensive. Twenty experiments, taking the retention time of the first peak, resolution between the second and third peaks and the peak area of the third peak as the responses with three important variables as acetonitrile concentration, buffer pH, and spray voltage, were used to design mathematical models. The experimental responses were fitted into a second order polynomial and the three responses were optimized to predict the optimum conditions for the effective separation of the studied compounds. The optimum conditions were acetonitrile and potassium dihydrogen ortho phosphate buffer (pH 6.8, 35:65%v/v) as the mobile phase and at a spray voltage of 2.740 V. The m/z range was found to be 481.05 → 113.25, 325.05, 585.15 → 229.10 for Telmisartan, Chlorthalidone and Metoprolol succinate respectively. The m/z range does not affect by acetonitrile concentration, buffer pH and spray voltage. The method showed a good agreement between the experimental data and predictive value throughout the studied parameter space. The optimized assay condition was validated according to the International Conference on Harmonization guidelines to confirm specificity, linearity, accuracy and precision