The emergence of anti-influenza A virus drugs resistant strain highlights the need for more effective therapy. Our earlier study demonstrated that c-jun, a downstream molecule of JNK, might be important in viral infections and inflammatory responses. In the present study, we explored the function of DNAzymes Dz13 that target c-jun in influenza A virus infected mice. Dz13 displayed non-toxic side effects on A549 cells and BALB/c mice. Moreover, Dz13-treated mice had enhanced survival after influenza compared with untreated mice. Simultaneously, the pulmonary inflammatory responses and viral burden were decreased in Dz13 treated mice. Furthermore, proliferation levels of infection-induced CD4+ and CD8+ T cells were impaired. These data demonstrated that Dz13 could reduce viral replication and inflammatory response in vivo, suggesting that Dz13 may potentially be used to treat influenza A viral infection.