The hydrophobicity of the membrane is paramount in membrane distillation (MD). In this study, novel hydrophobic oleic acid-3-aminopropyltriethoxysilane-functionalized multi-walled carbon nanotubes (OA-APTES-MWCNTs) were successfully synthesized and incorporated into polystyrene (PS)/polyvinylpyrrolidone (PVP) membranes as nanofillers to obtain modified mixed matrix membranes (MMMs) for vacuum membrane distillation (VMD) process. FTIR spectroscopy and TEM micrographs confirmed the successful synthesis of OA-APTES-MWCNTs. The synthesis membrane-VMD performance relationship was explored by statistically analyzing the effects of PS, PVP, and OA-APTES-MWCNTs concentrations in the dope solution using response surface methodology (RSM) with Box-Behnken design (BBD). BBD results showed that increasing any of the three factors in the membrane composition lowers water flux but with different intensities. NaCl rejection increases with PS and peaks with PVP and OA-APTES-MWCNTs concentrations. The optimal membrane composition was found to be 25 wt% PS, 0.731 wt% OA-APTES-MWCNTs, and 1.568 wt% PVP, achieving 99.00 % NaCl rejection and 12.34 LMH water flux. Adding OA-APTES-MWCNTs improved hydrophobicity, porosity, and surface roughness and thus water flux and NaCl rejection, but reduced mechanical strength compared to the PS (25 wt%)/PVP (1.568 wt%) membrane. These enhancements are critical for improving the efficiency and effectiveness of the VMD process.