Asimple, rapid isocratic liquid chromatography method was developed for the simultaneous determination of diphenhydramine, promethazine, chlorpheniramine, and ephedrine in cold-cough syrups commonly available in the Kenyan market. The influence of the percentage of organic modifier, ion pairing agent, buffer concentration as well as pH and column temperature on the selectivity with respect to analytes was investigated. Optimum chromatographic separation was achieved using a C18 Gemini® NX column (250 mm × 4.6 mm, 5 μm) maintained at 40°C and a mobile phase comprising methanol – triethylamine – 0.2 M ammonium acetate pH 5.0 – water mixture (50 : 0.15 : 40 : 9.85, v/v) delivered at a flow rate of 1.0 mL/min. Upon validation, the proposed liquid chromatography method satisfied the International Committee on Harmonization acceptance criteria for linearity, sensitivity, precision, and robustness. The method was applied in the analysis of commercial samples obtained from Nairobi County, Kenya. The method can be used in routine analysis of cold-cough syrups containing the specified compounds.