Abstract This paper is related to the previous work (Manenti et al., “Parametric Simulation and Economic Assessment of Heat Integrated Geothermal Desalination Plant”, Desalination, 317, 193–205, 2013) and extends the steady-state simulation and process layout optimization by investigating the procedure to start up multi-effect distillation (MED) desalination plants. The operations involved in the startup procedure, such as seawater supply, energy supply and vacuum generation along the process are considered together with the status of controls to prevent any possible overlapping of these relevant aspects. Segregation of the operations is demonstrated to be essential to prevent any redundancy in the oscillatory behavior of process units that can easily lead to dangerous instabilities of the plant. Moreover, whenever geothermal sources are used for sustainable production of desalinated water, it is fundamental to account for some peculiarities such as certain limitations in controllability and operability of the geothermal source. General guidelines to start up desalination processes are provided; special attention is given to geothermal-supplied plants.