The excessive activation of interferon regulatory factor 7 (IRF7) promotes the development of acute lung injury (ALI) caused by influenza A virus (IAV). However, the deficiency of IRF7 increases the susceptibility to deadly IAV infection in both human and mice. To test whether the attenuation rather than the abolishment of IRF7 activity in local infectious sites could alleviate IAV-induced ALI, we established IAV-infected mouse model and trachea/lung tissue culture systems, and designed two IRF7-interfering oligodeoxynucleotides (IRF7-rODNs), IRF7-rODN M1 and IRF7-rODN A1, based on the mouse and human consensus sequences of IRF7 binding sites of Ifna/IFNA genes, respectively. In the model mice, we found a close relationship between the IAV-induced ALI and the level/activity of IRF7 in local infectious sites, and also found that the reduced IRF7 level or activity in lungs of the mice treated with IRF7-rODN M1 led to the decreased mRNA levels of Ifna genes, the reduced neutrophil infiltration in the lungs and the prolonged survivals of the mice. Furthermore, we found that the effects of IRF7-rODN M1 on alleviating IAV induced ALI could be correlated to the reduced translocation of IRF7, caused by the IRF7-rODN M1, from cytosol to nucleus in IAV infected cells. These data suggest that the proper attenuation of IRF7 activity in local infectious sites could be a novel approach for treating the IAV-induced ALI.