The objective of the present work is to find out the optimal mass flux of two common refrigerants, R32 and R410A, undergoing boiling in an evaporator tube based on the entropy generation minimization approach. An entropy generation model is developed for two-phase boiling flow based on the drift flux approach. The distinct terms for entropy generation due to heat transfer and pressure drop are developed. The optimal solutions of the present model under a practical range of parametric conditions are compared with that obtained from the existing homogeneous and separated flow-based model. Analysis reveals that increasing the evaporator diameter and heat flux increases the optimal mass flux at minimum entropy generation for both refrigerants. On the other hand, increasing the evaporator length decreases the optimal mass flux. It is observed that the optimal mass flux data for all parametric conditions deviate within 10–15% on the positive and negative sides for drift flux and homogeneous models, respectively, compared to separate flow model. The present analysis also reveals that the overall deviation of data of the drift flux model and homogeneous flow model indicates a standard deviation of 1.95–1.98%, respectively.