In the study, fully atomistic molecular dynamics simulations were performed to investigate interactions between water molecules and several surfaces modeling for unmodified and modified parylene C surfaces. The introduction of −OH, −CHO, and −COOH to the surface and alterations in their coverage significantly influence the energetics of interactions between water molecules and the polymer surface. The theoretical studies were complemented with experimental measurements of contact angle, surface free energy, and imaging of osteoblast cells adhesion. Both MD simulations and experiments demonstrate that the optimal interface, in terms of biocompatibility, is obtained when 60% of native −Cl groups of parylene C surface is exchanged for −OH groups. By exploring idealized models of bare and functionalized parylene C, we obtained a unique insight into molecular interactions at the water–polymer interface. The calculated values of interaction energy components (electrostatic and dispersive) correspond well with the experimentally determined values of surface free energy components (polar and dispersive), revealing their optimal ratio for cells adhesion. The results are discussed in the context of controllable tuning and functionalization of implant polymeric coating toward improved biocompatibility.