Naproxen is a Non steroidal simultaneous anti inflammatory drug (NSAID) used in the treatment of pain or inflammation caused by conditions such as arthritis, ankylosing spondylitis, tendinitis, bursitis, gout, or menstrual cramps. Esomeprazole is used to treat gastro esophageal reflux disease. A simple, precise cost effective and stability indicating RP-HPLC method has been developed and validated for the determination of both Naproxen and Esomeprazole in pharmaceutical compositions. Separation of Naproxen and Esomeprazole from its potentional degradants were achieved within a shorter run time with required resolution, accuracy and precision thus enabling the utility of the method for routine analysis. The chromatographic separation was achieved on a Xterra RP-18 column (150 × 4.6 mm, 5μ) using a mobile phase consisting buffer prepared with 0.005 mole of sodium perchlorate, 5 mL N-butyl amine in milli-Q grade water with a pH of 8.7 which is mixed with Acetonitrile and Methanol at a flow rate of 1.5 mL per minute. Wavelength chosen for detection is 305 nm. The retention times of Naproxen and Esomeprazole peaks are around 3 and 6 minute respectively. The method was found to be linear over the range of 100.28 to 902.520 μg per mL for Naproxen and 9.6 to 45.6 μg per mL for Esomeprazole. The proposed method is validated as per the ICH and USP guidelines.