In this study, 3-D numerical simulations are conducted for single-phase flow and conjugate heat transfer in mini-channel heat sinks subjected to constant heat flux. The effects of using different gallium alloys (EGaInSn, EGaIn, GaSn, and GaIn) and various substrate materials (copper alloy, aluminum, tungsten, and silicon) on the temperature distribution, pumping power, pressure drop, maximum heat flux, and the total thermal resistance are comprehensively investigated for a series of Reynolds number (300–1900). Among all coolants considered, it is found that EGaIn reduces the flow resistance most efficiently. It is also found that the substrate material’s conductivity significantly influences the thermal resistance of the mini-channel. The higher conductivity leads to lower thermal resistance. In addition, when comparing to other gallium alloys, the GaIn alloy with higher thermal conductivity and specific heat shows better thermal performance. Finally, numerical results of the pumping power and pressure drop for gallium alloys are compared and discussed with the prediction by analytical correlations.