BACKGROUND: Respiratory viruses, such as influenza viruses and SARS-CoV-2, cause severe infections of the respiratory system. Cohort studies and clinical observations indicate that patients with severe influenza A virus (IAV) infections are at an increased risk of developing an ischemic stroke event. However, the underlying mechanisms remain elusive. To this end, we investigated the consequences of IAV infection on cerebral damage in a mouse model of ischemic stroke. METHODS: We intranasally inoculated male C57BL6/N mice with the mouse-adapted IAV strain A/Puerto Rico 8/34 or PBS as a vehicle control. At 3, 7, and 10 days post-infection, mice were subjected to transient middle cerebral artery occlusion, followed by sacrifice 24 hours after reperfusion for subsequent analysis. The anticoagulant drug acetylsalicylic acid was administered as treatment 1 day before transient middle cerebral artery occlusion. RESULTS: Our research demonstrated a time-dependent deterioration of cerebral ischemia after transient middle cerebral artery occlusion, resulting in increased infarct volume and a worsened neurological outcome at the propagation and inflammation phases of infection. Our observations revealed an elevation in procoagulant activity and an increase in thrombosis within the microvasculature after infection and stroke. This effect was attributed to an infection-mediated inflammatory milieu and accelerated neutrophil response. Upon infection, the release of increased neutrophil extracellular traps by neutrophils had detrimental consequences for transient middle cerebral artery occlusion development. Administration of acetylsalicylic acid or control antiviral therapy prevented the IAV-induced exacerbation of stroke and reduced brain damage by reducing NETosis and coagulation. CONCLUSIONS: These findings suggest that IAV infections enhance the systemic propensity for NETosis and foster a procoagulant state, thereby increasing the risk of cerebral damage and thrombosis following stroke. Targeting a combination of neutrophils and coagulation molecules simultaneously represents a promising treatment approach for clinical stroke.