The present work describes development and validation of a high-performance liquid chromatography–diode array detection (HPLC–DAD) procedure for the analysis of phenylephrine hydrochloride (PHE), paracetamol (PAR), caffeine anhydrous (CAF), cetirizine Dihydrochloride (CET), nimesulide (NIM) in pharmaceutical mixture. Effective chromatographic separation of PHE, PAR, CAF, CET and NIM was achieved using a Kinetex-C18 (4.6 mm, 150 mm, 5 mm) column with gradient elution of the mobile phase composed of 10 mM phosphate buffer (pH 3.3) and acetonitrile. The elution was a three step gradient elution program step-1 started initially with 2% (by volume) acetonitrile and 98% phosphate buffer (pH 3.3) for first 2 min. In step-2 acetonitrile concentration changed linearly to 20% up to 12 min the analysis was concluded by step-3 changing acetonitrile to 2% up to 20 min. The proposed HPLC method was statistically validated with respect to linearity, ranges, precision, accuracy, selectivity and robustness. Calibration curves were linear in the ranges of 5–100, 100–1000 and 10–200 mg/mL for PHE, PAR, CAF, CET and NIM respectively, with correlation coefficients >0.9996. The HPLC method was applied to tablet dosage form in which the analytes were successfully quantified with good recovery values with no interfering peaks from the excipients.