Nanoparticle (NP) surface properties define how engineered nanomaterials interact with proteins. In aqueous systems, these interactions are driven by the binding of water to NPs and proteins. Understanding the true nature of this NP–water interface and its involvement in the properties of nanomaterials is a fundamental challenge in nanotechnology. Here, we review recent studies on the involvement of water molecules in the interaction of NPs with proteins. We first address the thermodynamic aspects of the NP–protein interaction and the means by which solvation shells can alter the nature of this phenomenon. We then discuss how the chemical nature of the NP surface affects the adsorption of water molecules and how this adsorption can either favor or inhibit protein–NP interactions.