The organic Rankine cycle (ORC) system powered by exhaust heat has great potential in improving engine performance. Many optimizations of the only ORC system were conducted, while the existing literature pays limited attention to the optimization of the engine-ORC combined system. By considering the importance of interaction, cooperation, and influence between the engine and ORC system, a global optimization of the diesel engine-ORC combined system (herein, the combined system) is conducted in this paper with respect to power output and fuel economy. A GT-Suite model of the combined system and a GT-Suite/Simulink co-simulation model are proposed to obtain the optimum operating parameters of the engine and the ORC system under various operating conditions. Furthermore, the effects of the operating parameters, namely, exhaust valve timing, injection timing, expander speed, and pump speed, are evaluated on the combined system. In addition, models of the engine and the ORC system are calibrated, and a particle swarm optimizer (PSO) is designed and adopted for global optimization. Optimization results show improvements of 3.24% and 3.13% on the power output and brake specific fuel consumption (BSFC), respectively, with full engine load when the engine is operated at 3600 r/min. In the optimization of fuel economy with partial engine load, a maximum reduction of 5.71% on the BSFC of the combined system is obtained at 3600 r/min engine speed.