Viral infections such as human papillomavirus, rotavirus, and cytomegalovirus continue to pose significant global health challenges, causing persistent and widespread disease. The objective of this study is to evaluate the preliminary in vitro antiviral and cytotoxicity profile of zinc oxide (ZnO) and copper oxide (CuO) nanoparticles, which were synthesized through a green approach using Moringa oleifera leaf extract, against these viruses. Regarding antiviral effects, ZnO nanoparticles demonstrated potent antiviral activity against HPV, CMV, and rotavirus, with high selectivity indices and lower cytotoxicity compared with copper oxide nanoparticles. For HPV and CMV, ZnO showed markedly higher CC₅₀ and SI values (HPV: SI = 10.67; CMV: SI = 10.57) than copper oxide nanoparticles, which exhibited lower selectivity and greater cytotoxicity. Against rotavirus, ZnO nanoparticles also exhibited superior safety and antiviral efficacy (CC₅₀ = 798.42 µg/mL; SI = 11.49), whereas copper oxide nanoparticles showed relatively higher toxicity and lower selectivity. In parallel, quercetin, the major flavonoid of Moringa oleifera, was evaluated in silico as a potential inhibitor of rotavirus VP5*, CMV UL44, and HPV E6 using molecular docking and 150 ns molecular dynamics simulations. Quercetin exhibited favorable binding affinity, stable interaction profiles, and low RMSD fluctuations across all viral targets. Overall, green-synthesized ZnO nanoparticles demonstrated promising preliminary antiviral activity with an improved safety profile compared with CuO nanoparticles, while the computational findings support quercetin as a potential multi-target antiviral candidate. Further studies using direct virological assays and in vivo models are required to validate these findings and elucidate the underlying antiviral mechanisms.