A detailed mathematical model, based on mass and energy balances, was developed in order to provide guide lines for the optimal design and operation of a vacuum-multi-effect membrane distillation system. Since there is no well-established solution for the V-MEMD system, two case studies were used for the feed channel. The comparison between experimental and theoretical values of distillate flux showed low deviations (1.9%-11.1%) for tap water as regards the second case study. However, the deviations were higher, in the range of 2%-23%, when saline water was used as feed solution. The model was also utilized to investigate the effect of the operating conditions, membrane structural properties and design parameters on the performance indicators. High values of the hot water inlet temperature and feed inlet temperature lead to increase of water productivity and recovery ratio. Membranes with high porosity, large pore size and low thickness are the best candidates for enhancing the water productivity. Introduction of spacer improves the mass and heat transfer in the channels of the system. Also, the increment of the number of effects from 2 to 4 significantly lowers the specific thermal energy consumption.