A simple and rapid spectrophotometric method is proposed for the determination of diphenhydramine hydrochloride in a pharmaceutical formulation. The method is based on ion-pair complexation with methyl orange (MO) at pH 3 .0 (phthalate buffer). The yellow ion-pair complex was extracted with chloroform and estimated at 420 nm. Validation parameters for the method were established following standard guidelines. The calibration curve was found to be linear over the range of 20 to 100 μg/ml with a correlation coefficient of 0.9822. The method gave good recovery with relative standard deviation (% RSD) of between 0.38 and 1.11 while precision was between 0.457 and 0.774 for inter-day and 0.556 and 0.908 for intra-day. The limit of detection (LOD) and limit of quantitation (LOQ) were 3.1 and 10.3 μg/ml respectively. The proposed method was found to produce results comparable to the official titrimetric method and so it was employed in the determination of diphenhydramine hydrochloride in a formulation with excellent results.