Influenza A virus (IAV) infection is associated with outcomes ranging from subclinical infection to severe pneumonia. In this study, we compared IAV strains BJx109 (H3N2), HKx31 (H3N2), and PR8 (H1N1), for their ability to elicit innate immune responses from mouse airway cells in vitro and their virulence in mice. The viruses differed markedly in their ability to induce disease in mice (PR8 > HKx31 > BJx109). In particular, PR8 infection was associated with high levels of virus replication and pulmonary inflammation. We next compared the ability of each virus strain to infect and induce inflammatory mediators from mouse airway cells. First, major differences were observed in the ability of viruses to infect and induce chemokines and cytokines from mouse alveolar macrophages (BJx109 > HKx31 > PR8), but not from airway epithelial cells (AEC) in vitro. Second, C-type lectins of the innate immune system in mouse lung fluids blocked the ability of BJx109, but not PR8, to infect mouse macrophages and AEC. The failure of the virulent PR8 virus to elicit responses from airway macrophages, combined with resistance to antiviral proteins in mouse airway fluids, likely contribute to virulence in mice. These findings provide insight into the mechanisms underlying disease severity in the mouse model of influenza infection.