This work addresses retrofitting the infrastructure of multiple-effect vacuum membrane distillation (V-MEMD) units by using cross-flow configuration (CFC). In this configuration, the feed water is evenly divided and distributed over the effects. In this case, the feed water stream for each effect is kept at a high temperature and low flow rate. This will lead to an increase in the vapor pressure gradient across the hydrophobic membrane and can also maintain the thermal energy of the stream inside the individual effect. It is found that CFC improves internal and global performance indicators of productivity, energy, and exergy. A mathematical model was used to investigate the performance of such a modification as compared to the forward-flow configuration (FFC). The cross-flow configuration led to a clear improvement in the internal performance indicators of the V-MEMD unit, where specifically the mass flux, recovery ratio, gain output ratio, and heat recovery factor were increased by 2 to 3 folds. Moreover, all the global performance indicators were also enhanced by almost 2 folds, except for the performance indicators related to the heat pump, which is used to cool the cold water during the operation of the V-MEMD unit. For the heat pump system, the specific electrical energy consumption, SEEC, and the exergy destruction percentage, Ψdes, under the best-operating conditions, were inferior when the feed water flow was less than 159 l/h. This can be attributed to the fact that the heat rejected from the heat pump system is not fully harnessed.