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The aim of this study is to explore the hydrothermal attributes of three types of nanofluid containing the silver nanoparticles, aluminum oxide nanoparticles, and hybrid silver–aluminum oxide nanoparticles in two different types of microchannel, namely Left-Right and Up-Down wavy microchannels. The multi-phase mixture model is utilized to numerically simulate the flow at constant pumping powers. The results unmask that the secondary flow formed due to the wavy structure is more severe for the Left-Right wavy microchannel compared to the Up-Down one. Also, a maximum 330% enhancement in the convective heat transfer coefficient was observed for the Up-Down wavy microchannel working with the silver nanofluid, while the same value for the Left-Right one was 200%. Although the impact of using the nanofluids is more dominant for the Up-Down wavy microchannel, the Left-Right one exhibited better cooling performance in terms of the Nusselt number. It was observed that utilizing the nanofluids has minor impact on improving the bottom surface temperature uniformity for the Left-Right wavy microchannel, while for the Up-Down one this effect is more dominant. Lower amounts of thermal resistance were obtained in the case of using the nanofluids for both wavy structures, with more impact on the Up-Down one. [ABSTRACT FROM AUTHOR]