This study aimed to evaluate the effects of operating parameters (temperature (Tf), Reynolds number (Re), and salinity (Cf) on wettability (contact angle, liquid entry pressure and surface free energy) and wetting indicators evaluated with the recently developed Detection of Dissolved Tracer Intrusion (DDTI) method in Vacuum Membrane Distillation (VMD) for desalination. A 0.22 μm PVDF membrane was subjected to VMD considering a large NaCl feed salinity (22 to 310 g/L). In a first step, the effects and interactions of the operating parameters on the totally wetted surface ratio (ωs) was studied using Box Behnken design of experiments. It was shown that for salt concentrations below 166 g/L the ωs is low and is poorly affected by Re and Tf, whereas for a salt concentration of 310 g/L the influence of Tf and Re becomes sensitive, and high Tf and high Re are required to avoid wetting. In a second step, the effect of salinity was evaluated as a proportion of the liquid intrusion. Here it appears that the range of salinity influences the wetting mechanisms, with an evidence of total wetting only for hypersaline concentrations (higher than 200 g/L).