•Performance models of pilot V-AGMD modules published for the first time.•Feed flow rate crucial for the performance of pilot V-AGMD.•Predictions of STEC improved by modelling direct temperature measurements.•Optimization of performance including costs for an MD facility.•Thermal energy cost influences critically LCOW and dimensioning of the facility. Membrane distillation using multi-envelope modules in vacuum enhanced air gap (V-AGMD) operation has been demonstrated as the best alternative to the current thermal desalination technologies. This work presents for the first time the use of response surface methodology (RSM) to model and validate the performance of V–AGMD operation for seawater desalination in three multi-envelope modules with different internal designs. Permeate productivity (PFlux) and condenser outlet temperature (TCO) were modelled and validated from results obtained in steady-state experiments, considering the evaporator inlet temperature, the condenser inlet temperature, and the feed flow rate as inputs. To gain accuracy in the estimations of thermal efficiency regarding previous works, a novel strategy was applied, consisting in calculating the specific thermal energy consumption (STEC) using the models of PFlux and TCO, developed from direct measurements. The models of the three modules were used to search the optimal operating conditions that minimize the levelized cost of water (LCOW) in a large-scale MD plant under different scenarios. Different costs of thermal and electrical energy were considered and their influence on the number of modules required in the facility was also discussed.