An economical plant-wide control has been designed and implemented for biodiesel production by reactive distillation. Two available degrees of freedom have been assigned, to control the active constraints. The main conclusions were: (1) the optimal operation with lower value of the cost function (−946.72 USD/min) was established with liquid reflux, vapor stream, and feed flow molar ratio Methanol/Triglycerides of 8.43 kmol/min, 4.52 kmol/min, and 333:25, respectively. Additionally, the Biodiesel European Quality Standards were largely satisfied (Total Glycerol 0.25 wt%), even it exists an over purification, (2) the plant-wide control designed presented an adequate performance, maintaining stable and robust to disturbances and set-point changes, as it always reaches requested reference. Finally, in this study, the Tyreus-Luyben tuning method was the best tuning method, as it takes the least of time to reach the steady state.