<p>Ω-shaped reentrant microchannels have showed promising merits to enhance heat transfer performance for microchannel heat sinks, whereas there is still no knowledge for the optimization of their structural parameters. To this end, multi-objective optimization combined with numerical simulation was performed in this work to optimize the structural parameters of Ω-shaped reentrant microchannels. The width of slot (<i>W</i>_<i>s</i>), the height of slot (<i>H</i>_<i>s</i>), and the radius of the circular cavity (<i>R</i>) of Ω-shaped reentrant microchannels were selected as the design variables. Thermal resistance (<i>R</i>_<i>t</i>) and pumping power (<i>PP</i>) were considered as two objective functions to evaluate the overall thermal performance. The optimization was performed by non-dominated sorted genetic algorithm-II (NSGA-II) and K-means clustering combined with Kriging response surface (KRS) model. The multi-objective optimization result showed that the optimized reentrant microchannels could achieve a good compromise between thermal performance and pumping power. The optimized reentrant microchannels induced a 35% reduction in thermal resistance and a 14.5% reduction in pumping power compared to the reference design. They induced a reduction of 20&#xa0;K in the wall temperatures and more uniform temperature distributions, and presented a reduction of 100 ~ 120&#xa0;Pa in pressure drop of each reentrant microchannel compared to the reference one. The findings of this study provided valuable design guideline for high-performance microchannels heat sinks.</p>