Numerical investigations were conducted to analyze the heat transfer characteristics in a single square minichannel with supercritical C10H22 (sC10H22) and supercritical CO2 (sCO2). A single symmetric minichannel with a square cross-section of 1 mm × 1 mm and a length of 400 mm was selected, the top surface of which is applied with a uniform heat flux from 100 to 300 kW/m2. The inlet temperatures are varied from 20 to 150 °C and the inlet mass fluxes are ranged from 300 to 500 kg/(m2·s) in the physical model. The flow and heat transfer processes of the fluids were simulated in COMOSOL Multiphysics® software with RANS k-ω low-Reynolds number turbulence model. Results show that the heat removal capacity of sCO2 at 8 MPa is superior, which is 8 times that of sC10H22 at 3 MPa at the inlet temperature of 20 °C. When the inlet temperature and heat flux increase, the heat transfer performance of sCO2 drops sharply, while the overall performance of sC10H22 rises steadily. It suggests that sCO2 is more suitable for the heat transfer process with high-efficient cooling system at a lower inlet temperature, while sC10H22 is capable of a stable and long-time heat transfer process at a higher inlet temperature.