Respiratory viral infections are the most common illnesses worldwide affecting people today. One of them is influenza virus (IV) that causes ongoing epidemics with high morbidity and variable mortality. The ability of IV to rapidly change allowed it to stay ahead of vaccination efforts. Novel therapeutic approaches are needed to fight influenza. We have previously described an extracellular oxidative antimicrobial mechanism utilized by the respiratory innate immune system to inactivate IV. The lactoperoxidase/thiocyanate system produces reactive oxygen species, mainly hypothiocyanite anions, that have strong antiviral properties against IV in vitro. Our main focus is to reveal the molecular mechanism by which hypothiocyanite inactivates influenza viruses and whether it also prevents in vivo infections. Our data shows that hypothiocyanite is able to inactivate several IV strains including A and B strains and those resistant to current antiviral ostetamivir therapies. This data was also backed up by neuraminidase activity assays showing no reduction in viral NA activity when exposed to hypothiocyanite. Additionally, pre/co-incubation of IV with hypothiocyanite prevents infection of a variety of host epithelial cells by the virus. The ability of IV to bind to target cells is also strongly reduced when exposed to hypothiocyanite. These results suggest that hypothiocyanite primarily targets the surface hemagglutinin molecules of IV to prevent viral binding to and infection of target cells. This hypothesis represents a novel mechanism of viral inactivation utilized by the immune system.