Heat transfer through microscale heat sinks is a promising solution for optimizing energy efficiency. The application of nanofluids further enhances heat exchange. In terms of improving thermal performance, reducing irreversibility’s within the available system is considered as an effective approach. This study investigates the impact of applying nanofluids in microchannels to minimize energy losses. The work focuses on detailed mathematical development, based on Bejan’s entropy generation rate equation. To evaluate thermal, frictional and total entropy generation numbers, various microchannel shapes are proposed using different nanofluids, under the effect of a constant heat flux. Theoretical analyses indicate that increasing the heat flux along the wall effectively reduces entropy generation. The use of nanofluids, particularly CuO-water, proves to be more effective in this reduction due to its high thermal conductivity. Using water-based nanofluids enhances the minimization of irreversibility.