This work describes the conceptual design and a pilot-scale validation of a reactive distillation column for tributyl citrate (TBC) production by esterification of citric acid (CA) with n-butanol (BuOH). The conceptual design was carried out using novel reactive residue curve maps for mixtures of six components. Subsequently, a computational sensitivity analysis based on validated kinetic and phase equilibrium models enabled identifying critical design and operating variables to assess during experiments. Further pilot-scale experiments were performed according to a Box–Behnken design. The highest productivity at the pilot scale was obtained for a reflux ratio of 0.17, a CA/BuOH mole ratio of 1:13, and a feed flow of the reactive mixture of 4.9 kg/h. These conditions resulted in a CA conversion above 98.8%, a TBC yield of 52%, and a productivity of 24.4 kg/h/m3. It was verified that the process can successfully operate with azeotropic BuOH as feedstock and a prereactor, improving selectivity toward TBC.