Matrix metalloproteinase-8 (MMP-8) regulates inflammatory responses, but its contributions to the pathogenesis of influenza A viral (IAV) disease are not known. Plasma MMP-8 levels were increased 30-fold in subjects infected with H1N1 or seasonal IAV and were inversely associated with the PaO2/FiO2 ratio, suggesting potential value as a candidate marker of lung injury severity that requires validation in larger cohorts. MMP-8 levels were elevated in the lungs of H1N1-infected wild-type (WT) mice and localized to airway epithelial cells, macrophages, and polymorphonuclear neutrophils (PMNs). H1N1-infected Mmp-8?/? mice exhibited lower mortality and reduced lung viral burdens, but developed more severe lung injury than WT mice. Gene expression profiling revealed enhanced necroptosis and an exaggerated immune response in the lungs of infected Mmp-8?/? mice. Infected Mmp-8?/? mice had increased airway epithelial necroptosis with higher pulmonary levels of Type I interferons (IFNs), and increased frequencies of Class II MHC molecule-expressing macrophages and CD4 and CD8 T cells, and higher levels of some Th1 cytokines. In vitro, MMP-8 cleaved IL-1β and IL-6, but not Type I IFNs. These findings suggest that Mmp-8 deficiency is associated with restricted influenza virus spread and increased lung injury, accompanied by enhanced Type I IFN-associated necroptotic signaling and augmented antiviral immune responses. The latter may partly involve loss of MMP-8-mediated processing of pro-inflammatory mediators. MMP-8 may represent a host-response target in severe influenza infection, although therapeutic strategies targeting MMP-8 will need to balance enhanced viral clearance against the risk of increased lung immunopathology.