The ability of sonication phenomena in facilitating separation of azeotropic mixtures presents a promising approach for the development of more intensified and efficient distillation systems than conventional ones. To expedite the much-needed development, a mathematical model of the system based on conservation principles, vapor–liquid equilibrium and sonochemistry was developed in this study. The model that was founded on a single stage vapor–liquid equilibrium system and enhanced with ultrasonic waves was coded using MATLAB simulator and validated with experimental data for ethanol–ethyl acetate mixture. The effects of both ultrasonic frequency and intensity on the relative volatility and azeotropic point were examined, and the optimal conditions were obtained using genetic algorithm. The experimental data validated the model with a reasonable accuracy. The results of this study revealed that the azeotropic point of the mixture can be totally eliminated with the right combination of sonication parameters and this can be utilized in facilitating design efforts towards establishing a workable ultrasonically intensified distillation system.