A novel, simple, sensitive and rapid spectrophotometric method has been developed for simultaneous estimation of Domperidone and Esomeprazole. The method involved solving simultaneous equations based on measurement of absorbance at two wavelengths, 267 nm and 300 nm, λmax of Domperidone and Esomeprazole respectively. Beer’s law was obeyed in the concentration range of 10-50 μg/ml for Domperidone for Esomeprazole 5-25 μg/ml. The method was found to be precise, accurate, and specific. The proposed method was successfully applied to estimation of Domperidone and Esomeprazole in combined tablets form with good accuracy and precision. The suggested methods were validated according to International Conference of Harmonization (ICH) guidelines and the results revealed that; they were precise and reproducible. All the obtained results were statistically compared with those of the reported method, where there was no significant difference.