This work investigates the thermohydraulic behavior and the rate of thermodynamic irreversibility of water-based Al2O3 and Al2O3 + CuO hybrid nanofluid (HNF) in a circular copper tube subjected to a constant heat flux (CHF) of 8625 W/m2. The fluids under discussion flow in a tube at inlet fluid temperatures of 30, 45, and 60 °C. The thermophysical characteristics of the Al2O3 and HNF were studied at various temperatures and concentrations. The Nusselt number (Nu), entropy generation number (EGN), and friction factor were determined for the HNF (0–1 vol%) at different ranges of Reynolds numbers (Re) from 7000 to 44,662. The outcome of the HNF for 1 vol% is compared with that of Al2O3 nanofluid (NF). The findings show that the maximum amplification of Nu is 51, 59, and 79.7% observed for 1 vol% of HNF compared to water at 30, 45, and 60 °C. The pressure drop (Δp) and exergy efficiency (ηexe) of HNF increases with concentration and Re. The friction factor of HNF rises with concentration; however, it reduces at higher Re. Total entropy generation (TEG) of HNF reduces at higher Re and concentration. The thermal performance factor (TPF) of HNF is determined at various inlet fluid temperatures. The highest and lowest TPF of 1.7 and 1.02 were found for 1 and 0.1 vol% of HNF at 60 and 30 °C, respectively. The novel regression equations were developed to estimate the Nu, TEG and friction factor of HNF. Overall, Al2O3 + CuO HNFs can be employed as an alternative fluids thermal system cooling.