Reaction and distillation separation processes are two indispensable operating units in the chemical industry. However, a large amount of waste heat can be produced due to the presence of the reaction and distillation processes with high-temperature nature. Thus, it is of great significance to improve the economic performances of the reaction-separation processes via recovering waste heat. In the work, the recovery of waste heat from different heat sources in the reaction and distillation processes using the organic Rankine cycle (ORC) system with different working fluids is investigated taking the cumene synthesis process as an example. First, two streams with higher temperature and larger flowrates from the reaction section and distillation section are determined as the driving heat sources, while the conceptual design of the ORC system assisted reaction-separation process is completed. And then, the operation parameters of the ORC system with two heat sources and eight working fluids including R113, R123, R245ca, R245fa, R600, R600a, R601, and R601a selected by heuristic rules are optimized, aiming to maximize the annual net economic revenues (NER) using the genetic algorithm. Following, the corresponding exergy analysis of the ORC schemes driven by two heat sources with different working fluids is performed. The results illustrate that the heat of heat sources from both reaction section and separation section should be utilized since the ORC system with mentioned eight working fluids can produce positive NER, and the stream from the reaction section is more suitable as the driving heat source of the ORC system compared to that from the distillation section due to higher temperature, greater flowrates, and the coexistence of both latent heat and sensible heat. Overall, working fluids R113 and R123 are the worthiest of consideration among mentioned eight working fluids in terms of NER produced and the thermodynamic efficiency (η) of the corresponding ORC system. However, the environmental damage factors of the working fluids R113 and R123 are not preferred compared to other working fluids. Comprehensively considering economic, environmental, and thermodynamic performances, R601 are the preferred working fluid to perform the recovery of waste heat from the cumene synthesis process using the ORC system. The corresponding NER are 17.98 × 104$/a and 1.90 × 104$/a, which are 9.78% and 5.00% lower than that of the ORC system using the most economic working fluid R113, and at least 8.44% (R601a) and 2.70% (R123) higher than that of the ORC system using other working fluids for two heat sources, respectively. The η of the ORC system with R601 as working fluid can reach 17.73% and 11.15% for two heat sources, respectively, are slightly lower than that of the ORC system using R113 (19.41%) and R123 (11.49%) as working fluids.