This study investigates the effects of incorporating copper (Cu), zinc oxide (ZnO), and zirconium dioxide (ZrO₂) nanoparticles at concentrations of 2.2, 4.3, and 8.7 wt.% on the tensile strength, water vapor transmission rate, and antimicrobial properties of polyethylene-based films (46 g base polymer). Polyethylene nanocomposites were prepared via melt extrusion. Results demonstrate that nanoparticle types and concentrations significantly influence composite performance through distinct mechanisms. Cu nanoparticles exhibited the most balanced enhancement, with optimal elongation and barrier performance at intermediate concentrations. With 4.3wt.% loading, ZnO nanoparticles improved tensile strength the most, while ZrO₂ nanoparticles demonstrated clearly mechanical reinforcement at lower loadings and performance degradation at higher concentrations due to particle agglomeration. Bacterial activities showed significant results at the highest loading concentration for all the nanoparticles. However, ZrO₂ achieved 94% reduction against both B. subtilis and E. coli at 2.2 wt.% loading surpassing Cu and ZnO. The incorporation of nanoparticles led to a reduction in water vapor transmission rates, with the best barrier properties noted at 4.3 wt.% for the Cu and ZnO types, excluding ZrO₂. This comprehensive analysis provides critical insights for designing multifunctional polyethylene nanocomposite films for packaging and biomedical applications.