The role of the retention strength of Cu⁰ and Ag⁰ nanoparticles on the induced antibacterial properties of montmorillonite and cellulose-supported polyol dendrimer was comparatively investigated. An unprecedented approach involving X-ray photoelectron spectroscopy, thermal analyses, and surface charge measurements allowed correlating the host–matrix features to the different antibacterial activities of Cu⁰ and Ag⁰ nanoparticles against both the bacterial strains. Optimal metal–matrix interactions appear to favor high dispersion of both metal particles and material grains, thereby improving the contact surface with the cultivation media. This was explained in terms of hydrophilic character and judicious compromise between the metal retention by the host–matrix and release in the impregnating media. Competitive Lewis acid–base interactions appear to occur between MNP, solid surface and liquid media. These findings are of great importance, providing a deeper understanding of the antibacterial activity of metal-loaded materials. This opens promising prospects for vegetal fibers and clay-supported drugs to treat dermatological and gastro-intestinal infections.