The emergence and rapid spread of SARS-CoV-2 variants have underscored the urgent need for innovative antiviral strategies. This study investigates the potential of gold and silver nanoparticles as effective agents against COVID-19 variants, including Alpha, Beta, Gamma, Delta, and Omicron. Nanoparticles possess unique physicochemical properties that enable them to interact with viral particles and disrupt crucial viral functions, making them promising candidates for antiviral therapy. Through advanced computational modeling, integrating techniques such as molecular dynamics simulations and quantum mechanical calculations, we explore the interaction dynamics between nanoparticles and key viral spike glycoprotein specific to each variant, which plays a pivotal role in host cell entry. Our analysis elucidates the mechanisms by which gold and silver nanoparticles interact with variant-specific targets, docking analysis underscores their notable affinity towards all five ACE2-spike receptor variants. Notably, the binding affinities range between 0.18 and 0.27 Kcal/mol, indicative of strong interactions. Across the complexes, AuNPs generally exhibit a slightly higher affinity compared to AgNPs. Furthermore, we investigate the physicochemical properties of nanoparticles, such as size, shape, and surface functionalization, that influence their antiviral efficacy against different variants. Our findings provide valuable insights into the design and optimization of nanoparticle-based therapeutics for combating the evolving landscape of COVID-19 variants.