The organic Rankine cycle (ORC) is regarded as one of the most promising methods to increase the efficiency of diesel engines. Owing to the variability of exhaust energy with engine speed and load, the ORC should be designed for various operating conditions of engines for optimal waste heat recovery (WHR). In this study, an integrated simulation model of the diesel engine-ORC combined system (the combined system) is built by GT-Suite. Based on the model, the MAPs of optimum parameters are obtained by an artificial neural network (ANN) and a genetic algorithm (GA). Subsequently, operation modes of the combined system under various conditions are proposed. Finally, a control strategy of switching operation modes and adjusting parameters that adapts to various conditions of diesel engines is developed by GT-Suite and MATLAB/Simulink. Simulation results show that the optimum pump speed is steady approximately 1000 r/min under the low load region of the engine and increases with the engine load when the engine speed is higher than 1800 r/min. By contrast, the optimum expander speed is 1500 r/min in all selected engine operating conditions. Further investigations indicate that the performance of the combined system presents improvements, with a 3.57% increase in thermal efficiency and a 10.09 g/(kW.h) reduction in brake specific fuel consumption (BSFC) when compared against the original diesel engine. These preliminary results prove that the integrated simulation model can be used for further research. Meanwhile, with regard to the proposed control strategy, more thorough experimental research needs to be conducted.