A simple, sensitive, and rapid HPLC method was developed for analyzing H1 receptor blockers viz, hydroxyzine, cetirizine, meclizine, loratadine, desloratadine, rupatadine and fexofenadine in bulk and drug products. Chromatographic separation was performed on Phenomenex cyano analytical column (150 mm x 4.6 mm i.d, 5 μm). D-optimal mixture design methodology, a chemometric tool was employed for chromatographic optimization. The mobile phase system comprising acetonitrile-methanol-ammonium acetate buffer (40 mM; pH 3.8 adjusted with acetic acid): 18/36/46% v/v/v respectively, was identified by using overlay plot of the design. Mobile phase delivered at 1.5 mL min-1 flow rate and peaks were detected at 222 nm. All analytes were baseline separated in less than 9.5 min. The proposed method was validated for linearity, accuracy, precision, limit of quantification, and robustness according to ICH Q2 (R1) guidelines. Calibration curves were linear over selected range (≥0.996) for all analytes. The proposed method was successfully applied for the quantitative analysis of seven commercially available tablet dosage forms. Good agreement was found between the assay results and the label claim of the marketed formulation by showing good %recovery and %CV. The study demonstrated that the proposed HPLC method can be employed for routine quality control purposes.