Packaging acts like a bond between visual communication and production technology. Packaging material is often coated to enhance visual appearance and some protective features. The COVID pandemic changed consumers’ behavior and understanding of the importance regarding the antimicrobial properties of goods that come in contact with hands. The aim of this research is to investigate and determine the antimicrobial properties of nanocomposite coatings which include nanosized zinc oxide (ZnO), titanium dioxide (TiO2), and silicon dioxide (SiO2). For the purpose of this research, a lithographic printed packaging was coated with a nanocomposite composed of flexographic water-based varnish with incorporated ZnO, TiO2, and SiO2 nanosized particles. A total of eight modulations were presented and compared to the lone water-based varnish. The results have shown that applying nanocomposites will increase the total surface free energy of the packaging surface but will decrease the polar component of the surface free energy leading to lower hydrophilic properties. Both nanocomposite types showed that the increase in the nanoparticle weight ratio leads to higher protection benefits. Nanocomposites with ZnO have better antimicrobial activity than the ones with TiO2. The Hybrid/Z (ZnO + SiO2) significantly improved the antimicrobial capacity of water-based varnish, primarily against the ubiquitous foodborne pathogen Listeria monocytogenes.