The pharmaceutical combination of dexpanthenol (DPA), lidocaine hydrochloride (LIH) and mepyramine maleate (MAM) is used for their anti-allergic, anti-inflammatory, anti-pruritic, anesthetic and antiseptic properties. The present study was aimed to develop and validate a new, first and rapid high performance liquid chromatographic method for simultaneous determination of DPA, LIH and MAM in the presence of their stress-induced degradation products in pharmaceutical gel/fluigel formulations. The chromatographic separation was performed on an Inertsil ODS-3 V, 250 × 4.6 mm (5 μm) column using a gradient mobile phase of an aqueous solution of ammonium acetate (0.01 M) and methanol mixture at gradient flow rates of 1.3 mL/min and 1.5 mL/min with detection at 230 nm. The retention times for DPA, LIH and MAM were ~3.28 min, 11.67 min and 12.99 min, respectively. The method was validated in accordance with International Conference on Harmonisation guidelines. Calibration curves were linear in the ranges of 9-54 μg/mL for MAM and LIH and 30-180 μg/mL for DPA with satisfactory correlation coefficients (R2 > 0.999). The mean % recoveries obtained were found to be 99.9% for MAM, 100.3% for LIH and 99.3% for DPA. Precision % RSD was <2. Robustness results were uniform, there were no marked changes, so method is highly validated. All drugs were subjected to stress conditions and degradation products were separated with acceptable peak tailing (T ≤ 2) and good resolution (Rs > 2). The validated method therefore can be adapted for quality control procedures of the drugs in pharmaceutical dosage forms and their stability studies.