The entropy generation and exergy efficiency of nanodiamond+Fe3O4 hybrid nanofluids in a circular tube are inspected experimentally. The hybrid nanofluids were prepared in a 60% ethylene glycol and 40% water by weight base fluid and their thermophysical properties were evaluated at different particle loadings and temperatures. The pumping power, friction factor, and heat transfer were evaluated at various particle loading (0.05% to 0.2%) and Reynolds number (2000 to 8000) as well. The results indicated that the thermal conductivity and viscosity are augmented by 14.65% and 79%, respectively at 0.2% particle loading and 60 °C compared to the base fluid. At a particle loading of 0.2% nanofluid and a Reynolds number of 7218, the following results are obtained compared to the base fluid data: the Nusselt number, frictional entropy generation, exergy efficiency, friction factor, and thermal performance factor are increased by 19.67%, 210.6%, 17.54%, 15.11%, and 14.19%, respectively; while the thermal entropy generation is decreased by 22.93%. New regression equations are modeled to evaluate the Nusselt number, friction factor, and thermophysical properties.