Polyhedral oligomeric silsesquioxane (POSS) reagents have unique hybrid chemical compositions containing nano-sized cage structures with dimensions comparable to those of most polymer segments and coils. This article reports a generalized functionalization scheme of POSS that is suitable as a nanohybrid with Nylon 6. The thermodynamic interaction energy density, thermodynamic solubility parameter, and activation energy of the specific interaction between Nylon 6 and POSS were examined. The mechanical, thermal, and morphological properties of the Nylon 6 nanohybrids were also analyzed and compared with the theoretical estimation.