Most therapeutic strategies for the development of antiviral agents are designed based on targets specific to each virus. We examined the potential broad-spectrum activity of antimicrobial peptoids (AMPs) against two different viruses. AMPs are mimetics of antimicrobial peptides, which are sequence-specific N-substituted glycine oligomers, where their side chains are appended to the backbone amide nitrogens rather than α-carbons. As a result, peptoids are not proteolyzed, and have improved biostability and bioavailability and reduced immunogenicity relative to natural peptides. AMPs exhibit potent in vitro activity against a wide variety of bacteria and fungi via disruption of microbial membranes as well intracellular binding to nucleic acids. Thus, we hypothesized that they also exhibit activity against enveloped viruses. HSV-1 is an enveloped DNA virus that causes topical lesions. Incubation of HSV-1 with a panel of AMPs demonstrates variable inactivation of the virus prior to infection of cultured epithelial cells. Peptoids with the best activity exhibited dose- and time-dependent inactivation of HSV-1. Lead compounds inactivate the virus within 30 minutes at µg/ml concentrations. Transmission electron microscopy shows that these compounds remove the viral envelope, similar to what is seen with detergent treatment. We also tested the compound against SARS-CoV-2, an enveloped RNA virus that causes COVID-19. Our results show a dose-dependent inactivation of this virus prior to infection of target cells. Cytotoxicity assays show little toxic effects when applied to the apical surface of well-differentiated air-liquid interface cultures of airway epithelial cells. These results indicate that AMPs are strong candidates for broad-spectrum antiviral agents.