This paper discusses a general procedure leading to the process optimization of Multiple Flashing Desalination processes (MSF). The optimal configuration is attained via a novel inverse-design approach that uses the global exergy efficiency as objective function. A fundamental methodological novelty of the proposed procedure is that it does not require the generation of a complete simulated set of results at each iteration step of the optimisation, because the objective function is computed by a functional extrapolation based on the Proper Orthogonal Decomposition (POD) method. With this method, the (often excessively taxing) computational cost for repeated numerical process simulations of incrementally different configurations is substantially reduced by replacing much of it by easy-to-perform matrix operations: a certain (small) number of initial process simulations is used only to calculate the basis of the POD interpolation and to validate (i.e., extend) the results. As the accuracy of a POD expansion critically depends on the allowable number of initial simulations (the “snapshots”), the computational intensity of our methodology is certainly not negligible: but, as successfully demonstrated in the paper for a strongly simplified but realistic MSF process design problem, the idea that, given a certain number of necessary initial process simulations, additional full simulations are performed only in the “right direction” indicated by the gradient of the objective function in the solution space, leads to a successful strategy at a substantially reduced number of simulations. This “economy” with respect to other classical “optimization” methods is basically due to the capability of the POD procedure to identify the most important “modes” in the functional expansion of the vector basis consisting of a subset of the design parameters used in the evaluation of the objective function.