The optimization of a nanofluid-cooled rectangular microchannel heat sink is reported. Two nanofluids with volume fraction of 1%, 3%, 5%, 7%, and 9% are employed to enhance the overall performance of the system. An optimization scheme is applied consisting of a systematic thermal resistance model as an analysis method and the elitist non-dominated sorting genetic algorithm. The optimized results showed that the increase in the particles volume fraction results in a decrease in the total thermal resistance and an increase in the pumping power. For volume fractions of 1%, 3%, 5%, 7%, and 9%, the thermal resistances were 0.072, 0.07151, 0.07075, 0.07024, and 0.070 K/Wfor the SiC-H2O while, they were 0.0705, 0.0697, 0.0694, 0.0692, and 0.069 K/W for the TiO2-H2O. The associated pumping power were 0.633, 0.638, 0.704, 0.757, and 0.807 W for the SiC-H2O while they were 0.645, 0.675, 0.724, 0.755, and 0.798 W for the TiO2-H2O. In addition, for the same operating conditions, the nanofluid-cooled system outperformed the water-cooled system in terms of the total thermal resistance (0.069 and 0.11 for nanofluid-cooled, and water-cooled systems, respectively). Based on the results observed in this study, nanofluids should be considered as the future coolant for electronic devices cooling systems.