Microchannel flat-tube heat exchangers are known for their high heat transfer efficiency and compact size. In practical applications, the predominantly adverse influence of insoluble impurities on the condensation process necessitates further exploration into the underlying mechanisms affecting the flow boiling process. The effect of common insoluble impurities on the flow boiling of R410A refrigerant in a microchannel flat-tube heat exchanger has been investigated, and variation of the impurity volume fraction on heat transfer, mass transfer, pressure drop, and bubble formation are analyzed. Additionally, an adaptive modification method for the mass transfer factor is proposed. The numerical model of flow boiling heat transfer in a microchannel is validated through experimental data and empirical correlations. Thermo-hydraulic performance evaluation incorporates efficiency index and area goodness ratio metrics. Results reveal that the presence of insoluble impurities complicates the boiling heat transfer mechanism by influencing bubble evolution and multiphase flow patterns. Air impurities at a volume fraction not exceeding 5% prove beneficial for enhancing flow boiling efficiency in microchannels; however, a 38.5% decrease in efficiency index is observed with 1% oil impurities present. Optimal thermo-hydraulic performance is achieved with approximately 2%–3% water impurities.