Three-dimensional numerical study is presented in this work that deals with thermo-hydrodynamic and entropy generation analysis of water-based nanofluids in recharging microchannel (RMC). Four different water-based nanofluids (Al2O3, CuO, SiO2, and ZnO) are considered with volume concentrations of 1–5% and nanoparticle diameters of 10–50 nm to understand their effect on thermo-hydrodynamic performance and entropy generation. Substrate bottom surface is subjected to a constant wall heat flux of 100 W/cm2 while coolant with Reynolds number range of 100–500 flows through the RMC. It is revealed that among all the nanofluids under investigation, water/Al2O3 provides enhanced thermal performance with higher effectiveness parameter (η), and it also shows reduced entropy generation. With increasing volume concentration of water/Al2O3 nanofluid, heat transfer coefficient increases, effectiveness parameter increases, and entropy generation reduces. Water/Al2O3 nanofluid with smaller nanoparticle diameter shows enhanced heat transfer coefficient and reduced entropy generation, whereas it shows decreased effectiveness parameter. This is attributed to increased pressure drop with decreasing particle diameter. This study suggests that an optimized combination of particle diameter and volume concentration should be chosen for using nanofluid-based coolants for high heat flux removal.