The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) variants continues to challenge global healthcare systems, necessitating the exploration of innovative therapeutic modalities. This study proposes a novel nasal treatment approach leveraging the antiviral properties of Beta-escin (B-escin), a natural compound, in conjunction with gold and silver nanoparticles. B-escin, extracted from horse chestnut seeds, exhibits notable efficacy against coronaviruses, while nanoparticles offer advantageous features for targeted delivery and stability enhancement. Through integrated computational analyses encompassing molecular docking, molecular dynamics simulations, and quantum mechanical calculations, we assess the potential of this combined strategy against prevalent COVID-19 variants, including Alpha, Beta, Gamma, Delta, and Omicron. Specifically tailored for nasal administration, our investigation emphasizes the synergistic interactions between B-escin and nanoparticles, elucidating their collective impact on variant-specific viral targets within the nasal mucosa. The computational results indicate augmented antiviral activity and target specificity when combining B-escin with gold (Au) and silver (Ag) nanoparticles, surpassing individual treatment efficacy. Moreover, we investigate the influence of nanoparticle characteristics, such as size, morphology, and surface functionalization, on the observed synergistic effects. These findings underscore the promise of developing a nasal treatment utilizing natural compounds and nanotechnology, offering a potential frontline defense against the diverse spectrum of SARS-CoV-2 variants.