Vacuum Membrane Distillation (VMD) has been shown to be a promising desalination approach when going beyond the application range of Reverse Osmosis. Multi-stage arrangements in particular benefit from system-inherent heat recovery and thus yield low specific energy demand. Nevertheless, these systems show a complex behavior and therefore require a careful design, especially for higher salt concentrations which provide significant vapor pressure reduction. Previous experimental studies showed a need for a reliable system simulation tool, which we derived and calibrated in this work. The focus was on accurate modeling of the physical behavior, especially the multi-staging, polarization effects and different salt solutions up to their solubility limit. The model calibration and verification were based on results yielded by a novel triple channel VMD bench scale test cell, as well as technical scale system results from experiments with a memsys 2/4-stage Multi-Effect Vacuum Membrane Distillation (MEVMD) plant. The developed model was able to reproduce the system behavior and provides a tool for system optimization while providing insight into channel coupling, pressure staging, and phenomena like self-reduction of the number of working stages with rising feed salt concentration.