Nanoparticles have significant potential as new candidates for generating new types of flotation reagents with unique performance for wettability design and control. Hence, this study explores the wettability of a glass surface covered with polystyrene nanoparticles at various surface coverage percentage using molecular dynamics simulations. To investigate wettability on the bare and coated glass surface, the dynamics of water molecules, contact angle, density distribution profile, and hydrogen bonding patterns are analyzed as substrate wettability indicators. The results reveal that both unrelaxed and relaxed forms of glass surface tolerate a strong asymmetric distribution of surface energy in general, due to charge accumulation on the surface leading the surface to strong hydrophilic behavior. However, unlike chemical collectors, partial covering of glass surface with cationic polystyrene nanoparticles up to 10% reduces the surface tension to a favorable level of hydrophobicity for flotation.