A simple, accurate, reliable and reproducible HPLC method was developed for the simultaneous determination of esomeprazole and domperidone in combined dosage forms. The method employed C18 phenomenex column, acetate buffer: acetonitrile: methanol (55:35:10) as mobile phase and detection was made at 290nm. The retention times were found to be 6.76 and 4.42 min for ESO and DOMPE respectively. The method was validated as per ICH guidelines. The method shows good linearity, accuracy, and precision, limit of detection and limit of quantification. The linearity range was found between 4-19 μg/mL for both ESO and DOMPE with relative standard deviation of 0.022 and 0.076 respectively. The value for LOD was found to be 0.3 μg/mL and 0.4 μg/mL and LOQ was found to be 1.5 μg/mL and 2.5 μg/mL for ESO and DOMPE respectively. The main recovery was found to be 99.81 ± 1.27 and 100.43 ± 1.15 for ESO and DOMPE respectively. The method was suitable for routine analysis of ESO and DOMPE both individually and in combined dosage forms.