A new, accurate, simple, rapid, inexpensive and sensitive RP-HPLC method has been developed for the quantification of esomeprazole and naproxen in tablet dosage form, the separation of these molecules is achieved on PHENOMENEX C18 – column (250 × 4.6mm, 5μm) using mobile phase Phosphate Buffer, Acetonitrile and Methanol in the ratio of 459:458:83) with by induction of 20μl sample. Wavelength is selected at 303nm with flow rate of 01ml/min. The retention time of Esomeprazole was found to be 3.0 and for Naproxen it was 8.2min. The linearity range is 89.6-134.4μg/ml and 4.8-7.2μg/ml for Naproxen and Esomeprazole magnesium trihydrate respectively. The correlation coefficient was 0.9999 for Esomeprazole and 0.9961 for Naproxen. The method is validated for Specificity, Accuracy, Precision, LOD, LOQ, Linearity, and Robustness.