Influenza A virus (IAV) causes outbreaks of seasonal influenza disease. The IAV hemagglutinin (HA) is a key viral protein that determines the subtype of the virus and mediates attachment and entry into host cells. HA and other viral proteins are also known to interact with a variety of host proteins during infection. These viral-host interactions may be associated with either proviral or antiviral outcomes, where interferon-stimulated genes (ISGs) play a key role in host antiviral defence. Herein, we conducted a mass spectrometry screen to investigate associations between viral HA and host proteins, including ISGs, during infection. We identified viral HA interacting with immunoresponsive gene 1 (IRG1) protein, which is a mitochondrial enzyme involved in regulating the production of reactive oxygen species. It is well characterised for its role during bacterial infection, as IRG1 produces the metabolite itaconate that can inhibit bacterial metabolism. A direct role for IRG1 in modulating IAV infection has not been previously described. We validated an interaction between the IRG1 and IAV HA proteins of different subtypes (H1, H3, and H5) using immunoprecipitation approaches. IRG1 displayed antiviral activity against seasonal strains of IAV when overexpressed in different cell types. We identified that IRG1 did not impact the early stages of IAV infection, as the IRG1 overexpressing cells were as equally susceptible to IAV infection as control cells. However, lower viral titres were detected in supernatants from IAV-infected IRG1 overexpressing cells compared to control cells. This suggests IRG1 has potential to inhibit the late stages of IAV infection. Ongoing studies are exploring the mechanism of IRG1-mediated antiviral activity, assessing the potential antiviral activity of IRG1 to other respiratory viruses, and screening for additional interactions between other IAV proteins and host proteins associated with proviral or antiviral outcomes.