Obese individuals are considered a high-risk group for developing severe influenza virus infection. While the exact mechanisms for increased disease severity remain under investigation, obese mouse models suggest that increased acute lung injury (ALI), potentially due to enhanced viral spread and decreased wound repair, are likely involved. We previously demonstrated that upregulation of the lung epithelial cell β6 integrin during influenza infection was involved in disease severity. Knocking out β6 (β6 KO) resulted in improved survival. Of interest, obese mice have increased lung β6 integrin levels at homeostasis. Thus, we hypothesized that the protective effect seen in β6 KO mice would extend to the highly susceptible obese mouse model. In the current study, we show that crossing β6 KO mice with genetically obese ob/ob mice (OBKO) resulted in reduced ALI and impaired viral spread, like their lean counterparts. Mechanistically, OBKO alveolar macrophages and epithelial cells had increased type I interferon (IFN) signaling potentially through upregulated type I IFN receptor expression, which was important for the enhanced protection during infection. Taken together, our results indicate that the absence of an epithelial integrin can beneficially alter the pulmonary microenvironment by increasing protective type I IFN responses even in a highly susceptible obese model. These studies increase our understanding of influenza pathogenesis in high-risk populations and may lead to the development of novel therapies.IMPORTANCE Obesity is a risk factor for developing severe influenza infection. However, the reasons for this are unknown. We found that the lungs of obese mice have increased expression of the epithelial integrin β6, a host factor associated with increased disease severity. Knocking out integrin β6 in obese mice favorably altered the pulmonary environment by increasing type I IFN interferon signaling resulting in decreased viral spread, reduced lung injury, and increased survival. This study furthers our understanding of influenza pathogenesis in the high-risk obese population and may potentially lead to the development of novel therapies for influenza infection.