The extensive use of microchannel heat exchangers in various industries has significantly increased the importance of refrigerant condensation flow within microchannels. The current study aims to provide a numerical model for entropy generation and exergy destruction rates during condensation flow inside the microchannels. This study presents a series of numerical simulations of condensing isobutane (R600a) in microchannels. Isobutane is an eco-friendly compound and a good alternative to environmentally hazardous refrigerants. The investigation focused on circular microchannels with different hydraulic diameters changing between 200 and 600 µm. The various mass fluxes (changing between 200 and 1200 kg/m2s) and inlet vapor qualities (from 0.3 to 0.9) were analyzed for a thorough evaluation. The numerical simulations employed the Volume of Fluid (VOF) method in combination with the Lee model, which manages phase changes at saturation temperature. Using the proposed numerical model, the entropy generation rate and exergy destruction of isobutane condensation flow inside the microchannel were numerically predicted. Predicted values were compared to the theoretically calculated actual values. Considering all simulations, the results indicate that the mean absolute percentage error (MAPE) for the simulated entropy at the outlet of the microchannel is 17.80%. The mean absolute errors associated with the entropy generation and exergy destruction rates were determined as 8.04 × 10–8 W/K and 2.39 × 10–5 W, respectively.