Conjugated heat transfer and hydraulic performance for nanofluid flow in a rectangular microchannel heat sink with LVGs (longitudinal vortex generators) are numerically investigated using at different ranges of Reynolds numbers. Three-dimensional simulations are performed on a microchannel heated by a constant heat flux with a hydraulic diameter of 160 μm and six pairs of LVGs using a single-phase model. Coolants are selected to be nanofluids containing low volume-fractions (0.5%-3.0%) of Al₂O₃ or CuO nanoparticles with different particle sizes dispersed in pure water. The employed model is validated and compared by published experimental, and single-phase and two-phase numerical data for various geometries and nanoparticle sizes. The results demonstrate that heat transfer is enhanced by 2.29-30.63% and 9.44%-53.06% for water-Al₂O₃ and water-CuO nanofluids, respectively, in expense of increasing the pressure drop with respect to pure-water by 3.49%-16.85% and 6.5%-17.70%, respectively. We have also observed that the overall efficiency is improved by 2.55%-29.05% and 9.78%-50.64% for water-Al₂O₃ and water-CuO nanofluids, respectively. The results are also analyzed in terms of entropy generation, leading to the important conclusion that using nanofluids as the working fluid could reduce the irreversibility level in the rectangular microchannel heat sinks with LVGs. No exterma (minimums) is found for total entropy generation for the ranges of parameters studied.