An innovative HPLC assay method was developed and validated for quantification of Dextromethorphan hydrobromide and Desloratadine simultaneously in monophasic liquid formulation, by preparing syrup containing 30 mg/5 ml of Dextromethorphan hydrobromide and 1.2 mg/ml of Desloratadine. The chromatographic severance was executed by gradient solution A and B. The composition of buffer solution A contains 0.05 M monobasic potassium, then to it added 1 ml triethylamine and adjusted the pH to 2.3 with orthophosphoric acid, Methanol was used as Solution B. The gradient elution was executed with Kromasil C8 (250 mm × 4.6 mm) column having 1.5 ml/min flow rate, 20 μl injection volume with UV-estimation at 254 nm for Dextromethorphan hydrobromide and DES. The current research was planned according to Box-Behnken design by utilizing design expert software, using four factors such as column temperature (A), flow rate (B), mobile phase-organic phase (C) and pH (D), correspondingly the selected response variables were Resolution between A and B i.e. Desloratadine and methyl paraben (Y1), tailing of Dextromethorphan hydrobromide (Y2) and tailing of Desloratadine (Y3). The parameters like, system suitability, linearity, accuracy, precision, robustness, limit of detection, limit of quantitation and ruggedness were analyzed to validate the developed method in accordance with current regulatory guidelines. This article is protected by copyright. All rights reserved.