Treatment of viral infections continues to be elusive owing to the variance in virus structure (RNA, DNA, and enveloped and nonenveloped viruses) together with their ability to rapidly mutate and garner resistance. Here we report a general strategy to prevent viral infection using multifunctional macromolecules that were designed to have mannose moieties that compete with viruses for immune cells, and basic amine groups that block viral entry through electrostatic interactions and prevent viral replication by neutralizing the endosomal pH. We showed that cells treated with the antiviral polymers inhibited TIM receptors from trafficking virus, likely from electrostatic and hydrogen-bonding interactions, with EC50 values ranging from 2.6 to 6.8 mg/L, depending on the type of TIM receptors. Molecular docking computations revealed an unexpected, and general, specific hydrogen-bonding interactions with viral surface proteins, and virus and cell binding assay demonstrated a significant reduction in infection after incubating virus or cells with the antiviral polymers. Moreover, the mannose-functionalized macromolecules effectively prevented the virus from infecting the immune cells. Representative viruses from each category including dengue, influenza, Chikungunya, Enterovirus 71, Ebola, Marburg, and herpes simplex were surveyed, and viral infection was effectively prevented at polymer concentrations as low as 0.2 mg/L with very high selectivity (>5000) over mammalian cells. The generality of these cooperative orthogonal interactions (electrostatic and hydrogen-bonding) provides broad-spectrum antiviral activity. As the antiviral mechanism is based on nonspecific supramolecular interactions between the amino acid residues and mannose/cationic moieties of the macromolecule, the ability to form the virus-polymer and polymer-cell assemblies can occur regardless of viral mutation, preventing drug resistance development.