Effective thermal management is a key for the continuous development of electronics, which are characteristics of modern life. It has a great effect on the lifetime, durability and reliability of these systems. A liquid-cooled microchannel heat sink is a compacted cooling part that used to provide better heat dissipation rates and low temperatures in electronic components. Nanofluids have been introduced as effective coolants to be employed in this type of heat sink to increase the heat dissipation rate. However, a comparative assessment of the thermal performance between commonly used nanofluids and water as coolants for microchannel heat sinks is still lacking. For this purpose, a computational fluid dynamics (CFD), non-isothermal, three-dimensional detailed model has been developed to simulate and analyze the fluid flow and heat transfer physiognomies. The results show that examining performance parameters as functions of Reynolds number is misleading since the thermophysical properties are different among each coolant, and that employing nanofluids in a microchannel heat sink is impractical as water is cheaper and safer.