Influenza is a highly contagious virus with most individuals showing recovery within a week after symptom onset. However, children, the elderly, and those with chronic health conditions are at high risk of developing serious complications. Extensive immune cell infiltration of the lung and massive production of pro-inflammatory cytokines can result in lung tissue damage and disruption, resulting in hypoxia and death. During the 2024-2025 influenza season in the USA, influenza caused an estimated 27,000-130,000 deaths. Our previous studies have shown that agents known to drive polarization of macrophages into the M2a phenotype mitigated inflammatory responses to influenza H1N1 A/PR/8/34 (PR8). Since IRS2 dampens the IL-4-induced differentiation to the M2a subtype, we sought to determine the impact of IRS2 on PR8 infection. Contrary to expectations, IRS2-/- mice exhibited enhanced susceptibility to PR8 when compared to IRS2+/+ mice, which was associated with a significant drop in blood oxygen saturation. Additionally, PR8 infection induced significantly greater inflammation in the lungs of IRS2-/- mice than IRS2+/+ mice. Conversely, viral replication was not significantly different. Significantly increased levels of the inflammatory mediator HMGB1 and airway epithelial cell denuding were observed in the lungs of IRS2-/- mice, with a concomitant decrease in M2a gene expression. Mice with myeloid-specific knockout of IRS2 showed no enhanced sensitivity to PR8, supporting the hypothesis that the major impact of IRS2-deficiency on host response to PR8 infection is not myeloid cell-intrinsic. Overall, these results suggest that in the absence of IRS2, airway epithelial cells are especially sensitive to influenza-induced damage through dysregulated inflammation, resulting in increased susceptibility during infection.