Hesperidin (HSP) is considered to be the most effective antimicrobial agent against SARS-CoV2 virus. The HSP was loaded onto ZnO nanoparticles that were successfully incorporated, via the hydrothermal method, into polyvinyl alcohol (PVA) for use as food packaging material. The hydrothermal method enabled the bioactive ZnO-HSP to be homogeneously dispersed in the PVA, which significantly increased the thermal stability of the matrix, while decreasing the softening temperature. The water holding capacity and water solubility of the obtained nanocomposites was reduced compared to the PVA. Finally, the ZnO-HSP antimicrobial agent contributed important antibacterial properties to the PVA and increased its antioxidant capacity against and pathogens. In addition, the nanocomposites had no cytotoxic/proliferative effects on cancer cells. All results showed promise that the PVA/ZnO-HSP nanocomposites would be an excellent alternative for food packaging applications.