Recently, functional nanomaterials with unique sizes, shapes, and surface chemistry have been fabricated for various applications in all facets of science and technology. Among these diverse nanomaterials, copper oxide nanoparticles (CuO NPs) have garnered considerable attention due to their unique physicochemical parameters and semiconductor properties. Doping various functional materials in CuO NPs and the fabrication of CuO nanofillers functionalized with natural or synthetic moieties delivers improved antibacterial efficacy in food packaging applications. Moreover, the bactericidal effect of modified CuO NPs against foodborne pathogens largely contributes to their usage in food packaging technology. Therefore, it is essential to fabricate effective antimicrobial CuO nanofillers with minimal or no adverse side effects. This review discusses the synthesis, characterization, surface modification, antibacterial properties, food packaging applications, and toxicological implications of the diverse CuO nanofillers integrated in films and composites. In addition, it highlights their adverse side effects and ways to combat adverse situations. The forthcoming generation is expected to lead a groundbreaking surge of inventive food packaging systems (FPS) based on CuO hybrid nanofillers in food packaging industries.