Prevention of thermal runaway and establishment of safeāeconomic operating conditions are crucial for the practical operation of single diffusionācontrolled liquidāliquid reactions occurring in isoperibolic semibatch reactors. Hence, in this study, a mutual informationābased multiple feature recognition criterion (MIāMFR) was innovatively proposed, for which the maximum relevance minimum redundancy approach was introduced in feature screening; in combination with the support vector machine algorithm, various thermal behaviors can be effectively recognized. On this basis, a series of boundary diagrams were established accordingly, the impact of the variation in model parameters on which was systematically explored. Subsequently, an improved generalized thermal safety region was developed by introducing the upper thresholds in normal and cooling failure scenarios. Meanwhile, the robustness and progressiveness of the established MIāMFR criterion were confirmed by comparison with other conventional criteria. Finally, MIāMFRābased procedures were constructed to identify thermal behaviors and optimize safeāeconomic operating conditions in practices, based on which the optimum operating conditions of toluene mononitration were obtained.