AbstractIn this study, a Grey‐box (GB) model was developed to predict the optimum mass flow rates of inlet streams of a Shell and Tube Heat Exchanger (STHE) under varying process conditions. Aspen Exchanger Design and Rating (Aspen‐EDR) was initially used to construct a first principle model (FP) of the STHE using industrial data. The Genetic Algorithm (GA) was incorporated into the FP model to attain the minimum exit temperature for the hot kerosene process stream under varying process conditions. A dataset comprised of optimum process conditions was generated through FP‐GA integration and was utilised to develop an Artificial Neural Networks (ANN) model. Subsequently, the ANN model was merged with the FP model by substituting the GA, to form a GB model. The developed GB model, that is, ANN and FP integration, achieved higher effectiveness and lower outlet temperature than those derived through the standalone FP model. Performance of the GB framework was also comparable to the FP‐GA approach but it significantly reduced the computation time required for estimating the optimum process conditions. The proposed GB‐based method improved the STHE's ability to extract energy from the process stream and strengthened its resilience to cope with diverse process conditions.