Highly pathogenic avian influenza infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression and acute lung injury. Pro-inflammatory stimuli are known to induce intracellular ROS by activating NADPH oxidase activity. This work presents novel findings relating to the mechanisms associated with induction of inflammatory cytokines and chemokines following infection with highly pathogenic avian influenza H5N1 virus and the newly emerged, low pathogenic avian influenza H7N9 virus. The study identified the importance of two signaling molecules, FoxO3 and the TAM receptor tyrosine kinase, Tyro3, in influenza virus-induced cytokine and chemokine overproduction. Among the influenza-stimulated cytokines, CCL5 was identified as a potential marker for overactive host immunity. The contribution of reactive oxygen species (ROS) to signaling events that control cytokine production was also assessed using apocynin, a Nox2 NADPH oxidase inhibitor. Apocynin reduced influenza-stimulated ROS production, promoting FoxO3 activity as well as SOCS1 and SOCS3 expression, reducing cytokine and chemokine levels. We propose that modulation of host immune responses with antioxidant and/or anti-inflammatory agents in combination with antiviral therapy may have therapeutic benefits.