Mini-channel heatsinks have proven useful in removing high heat fluxes from microelectronic devices. However, further miniaturization of electronic devices requires significant enhancement in the mini-channel heatsinks’ thermohydraulic characteristics, which depend greatly on the coolant and geometrical configuration of the channel. Therefore, the current study explores the potential of mini-channel heatsinks’ using different coolants (water, nanofluid and supercritical carbon dioxide) and various channel configurations. The effect of various channel configurations on the thermohydraulic characteristics of the mini-channel heat sinks is evaluated numerically for different coolants employing three flow rates (17 g/s, 34 g/s and 50 g/s). Hence, the effects of fin height, spacing and thickness, and mass flow rate on the overall heat transfer coefficient (CHT) and pressure drop (ΔP) are reported for the abovementioned coolants. It is found that increasing the mass flow rate increases both the CHT and ΔP. It is also noted that increasing the fin height and spacing decreases both the CHT and ΔP, as opposed to increasing the thickness, which causes both the CHT and ΔP to increase. Among the three coolants used, the sCO2 shows superior performance compared to the water and nanofluid and this based on higher CHT and lower ΔP. Moreover, the performance evaluation criterion (PEC) for the sCO2 is higher than that for the water and nanofluid by 53% at 17 g/s flow rate and 243% at 50 g/s flow rate.