Understanding nanoparticle diffusion within non-Newtonian biological and synthetic fluids is essential in designing novel formulations (e.g. nanomedicines for drug delivery, shampoos, lotions, coatings, paints, etc.), but is presently poorly defined. This study reports the diffusion of thiolated and PEGylated silica nanoparticles, characterized by small angle neutron scattering, in solutions of various water-soluble polymers such as poly(acrylic acid) (PAA), poly(N-vinyl pyrrolidone) (PVP), poly(ethylene oxide) (PEO) and hydroxyethylcellulose (HEC), probed using NanoSight nanoparticle tracking analysis. Results show that the diffusivity of nanoparticles is affected by their dimensions, medium viscosity and in particular by specific interactions between nanoparticles and the macromolecules in solution; strong attractive interactions such as hydrogen bonding hamper diffusion. The water-soluble polymers retarded diffusion of thiolated particles in the order: PEO > PVP > PAA > HEC whereas for PEGylated silica particles retardation was in the order: PAA > PVP = HEC > PEO. In the absence of specific interactions with the medium, PEGylated nanoparticles exhibit enhanced mobility compared to their thiolated counterparts despite some increase in their dimensions.