Industrial effluents often contain azeotropic mixtures that are difficult to separate by conventional distillation. An illustrative case is the methanol/methyl acetate/ethyl acetate (MA/ME/EA) mixture. To address these challenges, this work studies the conceptual design and optimization of the reactive distillation-based hybrid processes for separating the MA/ME/EA mixture with an EA-rich feed composition (0.25/0.20/0.55 mol fraction). An improved triple-column extractive–reactive distillation with a side-draw product (TCERD-SP) and its heat-integrated variant (TCERD-SP-HI) have been developed. In the TCERD-SP process, EA is strategically withdrawn as a side product, reconfiguring the extractive column into integrated pre-separation and entrainer-recovery sections, thereby reducing entrainer and energy demands. A four-step process design methodology is applied, including thermodynamics analysis, conceptual design, rigorous optimization via Aspen Plus integrated with the genetic algorithm to minimize total annual cost (TAC), and comparative evaluation of economic and environmental performance. The results show that the basic double-column pre-separation-reactive distillation (DCPSRD) process, optimal for a previous feed composition, exhibits unsatisfactory TAC performance for this EA-rich feed composition. Among the configurations studied, the TCERD-SP process exhibits superior performance, saving TAC by 8.4% and 14.4% compared to the TCERD and DCPSRD processes, respectively. In addition, based on the advantage of convenient heat integration between the side reboiler and the reactive distillation column condenser, the heat-integrated TCERD-SP-HI process achieves a further 10.7% TAC reduction. Thus, for this EA-rich feed examined in this work, the TCERD-SP and TCERD-SP-HI processes are demonstrated as effective solutions for recovering these valuable chemicals.