Global energy agencies and commissions report a sharp increase in energy demand based on commercial, industrial, and residential activities. At this point, we need energy-efficient and high-performance systems to maintain a sustainable environment. More than 30% of the generated electricity has been consumed by HVAC-R units, and heat exchangers are the main components affecting the overall performance. This study combines experimental measurements, numerical investigations, and ANN-aided optimization studies to determine the optimal operating conditions of an industrial shell and tube heat exchanger system. The cold/hot stream temperature level is varied between 10 ℃ and 50 ℃ during the experiments and numerical investigations. Furthermore, the flow rates are altered in a range of 50–500 L/h to investigate the thermal and hydraulic performance under laminar and turbulent regime conditions. The experimental and numerical results indicate that U-tube bundles dominantly affect the total pumping power; therefore, the energy consumption experienced at the cold side is about ten times greater the one at the hot side. Once the required data sets are gathered via the experiments and numerical investigations, ANN-aided stochastic optimization algorithms detected the C10H50 scenario as the optimal operating case when the cold and hot stream flow rates are at 100 L/h and 500 L/h, respectively.