In recent decades, epidemics and pandemics have multiplied throughout the world, with viruses generally being the primary responsible agents. Among these, influenza viruses play a key role, as they potentially cause severe respiratory distress, representing a major threat to public health. Our study aims to develop new broad-spectrum antivirals against influenza to improve the response to viral disease outbreaks. We engineered macromolecules (named CD-SA) consisting of a β-cyclodextrin scaffold modified with hydrophobic linkers in the primary face, onto which unitary sialic acid epitopes are covalently grafted to mimic influenza virus−host receptors. We assessed the antiviral efficacy, mechanism of action, and the genetic barrier to resistance of this compound against influenza in vitro, ex vivo, and in vivo. We demonstrated that CD-SA, with a unitary SA, without extensive polysaccharides or specific connectivity, acts as a potent virucidal antiviral against several human influenza A and B viruses. Additionally, CD-SA displayed antiviral activity against SARS-CoV-2, a virus that also relies on sialic acid for attachment. We then assessed the genetic barrier to resistance for CD-SA. While resistance emerged after six passages with CD-SA alone, the virus remained sensitive through eight passages when co-treated with interferon-λ1 (IFN λ1). Finally, we completed the characterization of the antiviral activity by conducting both ex vivo and in vivo studies, demonstrating a potent antiviral effect in human airway epithelia and in a mouse model of infection, higher than that of Oseltamivir, a currently approved anti-influenza antiviral. The findings presented in this study support the potential therapeutic utility of a novel β-cyclodextrin-based nanomaterial for the treatment of influenza infections and potentially other sialic acid-dependent viruses.