Energy integration has been a research hotspot for decades, especially in the field of high energy consumption, like the chemical industry, and many methods for energy integration of process systems have been developed, such as heat exchange network synthesis and work-heat exchange network synthesis. There is still a considerable amount of medium and low-temperature waste heat that has not been effectively utilized in actual industrial production. In response to this problem, studies for the integration of the Organic Rankine Cycle (ORC) and process have been carried out. However, the relevant studies mostly focus on the coupling of ORC and heat exchange network for the recovery of waste heat and do not consider the effect of work production/consumption of the process streams, which neglects the influence of work-heat interaction on the coupling of ORC and work-integrated heat exchange network. This paper optimizes the integration of ORC and process stream with pressure/temperature change and designs a work-integrated heat exchange network. A two-layer genetic algorithm (GA) optimization strategy is proposed to determine the synthesis of heat exchange networks. The outer layer is to optimize the configurations of ORC, and the inner layer is to use an extended Duran-Grossmann model to determine the minimum utility consumption and the inlet temperature of the pressure-change sub-streams with the minimum exergy consumption as the objective function. Finally, the work-integrated heat exchange synthesis coupled with ORC is realized by an example study.