The thermal performance enhancement of a vertical helical coil heat exchanger using distilled water-based copper oxide-graphene hybrid nanofluid has been analyzed experimentally. Accordingly, the focus of this study is the preparation of CuO-Gp (80-20%) hybrid nanoparticles-based suspensions with various mass fractions (0% ≤ wt ≤ 1%). The volume flow rate is ranged from 0.5 L·min−1 to 1.5 L·min−1 to keep the laminar flow regime (768 ≤ Re ≤ 1843) and the supplied hot fluid’s temperature was chosen to equal 50 °C. To ensure the dispersion and avoid agglomeration an ultrasound sonicator is used and the thermal conductivity is evaluated via KD2 Pro Thermal Properties Analyzer. It has been found that the increment in nanoparticles mass fraction enhances considerably the thermal conductivity and the thermal energy exchange rate. In fact, an enhancement of 23.65% in the heat transfer coefficient is obtained with wt = 0.2%, while it is as high as 79.68% for wt = 1%. Moreover, increasing Reynolds number results in a considerable augmentation of the heat transfer coefficient.