A generalized functional group of polyhedral oligomeric silsesquioxane (POSS) suitable for various polymer systems, e.g., polyolefins, polyesters and polyamides, is presented using theoretical and experimental approaches to examine thermodynamic interaction between a polymer and POSS. Both Flory-Huggins interaction parameter and maximum difference of the solubility parameter are utilized to study theoretically specific interaction between polymers and POSS nanoparticles. Flory-Huggins interaction parameter was estimated by the melting point depression method determined by DSC, while maximum difference of the solubility parameter was predicted using the method of Hoftyzer and van Krevelen. The interaction characteristics of the polymer/POSS nanohybrids are further tested by measuring the activation energy with the Kissinger method, in which the activation energy was calculated using the temperature at the maximum degradation rate observed TGA. Viscoelastic, dynamic mechanical, thermal and mechanical properties of the polymer/POSS nanohybrids were also examined to correlate the theoretical and experimental results, finding that the isobutyl group was the most suitable functional group of POSS for polyethylene, poly(ethylene terephthalate), and Nylon 6.