In this study, the numerical conjugate heat transfer and hydraulic performance of nanofluids flow in a rectangular microchannel heat sink (RMCHS) with longitudinal vortex generators (LVGs) was investigated at different Reynolds numbers (200–1200). Three-dimensional simulations are performed on a microchannel heated by a constant temperature with five different configurations with different angles of attack for the LVGs under laminar flow conditions. The study uses five different nanofluid combinations of Al2O3 or CuO, containing low volume fractions in the range of 0.5% to 3.0% with various nanoparticle sizes that are dispersed in pure water, PAO (Polyalphaolefin) or ethylene glycol. The results show that for Reynolds number ranging from 100 to 1100, Al2O3–water has the best performance compared with CuO nanofluid with Nusselt number values between 7.67 and 14.7, with an associated increase in Fanning friction factor by values of 0.0219–0.095. For the case of different base fluids, the results show that CuO–PAO has the best performance with Nusselt number values between 9.57 and 15.88, with an associated increase in Fanning friction factor by 0.022–0.096. The overall performance of all configurations of microchannels equipped with LVGs and nanofluid showed higher values than the ones without LVG and water as a working fluid.