The organic Rankine cycle (ORC) is a promising method of recovering the exhaust heat of the internal combustion engine (ICE). However, the off-design exhaust conditions and the negative effects (such as increased backpressure and added weight) of the ORC installation onto vehicles greatly deterioratetheperformanceof ORC applied on mobile vehicles. In this paper, the ORC thermodynamic model with an integrated plate heat exchanger model is developed to evaluate the effects of sizing the heat exchanger and designing the ORC operating conditions on the thermodynamic performance of the ORC system. Considering various major exhaust conditions and the negative impacts of ORC system installation on vehicles, an optimal ORC system design strategy is proposed to maximize the net output power. The optimum geometric parameters of heat exchangers and ORC operating conditions are simultaneously designed through a mixed integer nonlinear programming problem. The proposed design strategy is compared with the design method without considering negative effects and the design method only based on one major engine operating point. The comparison results indicate that the proposed design strategy increases the weighted net output power and the proposed design strategy can ensure that the ORC works normally in various exhaust conditions. Among all the operating parameters, the size of the heat exchanger (two geometric parameters) is the major factor affecting the performance of ORC. These findings highlight the importance of considering various exhaust conditions and the negative impacts of vehicle-mounted ORC during the design procedure.