In mammals, IFN regulatory factor (IRF) 1 can activates cellular genes and promotes viral resistance against some DNA and RNA viruses. Most IRFs have been identified as critical regulators in the IFN responses in both mammals and fish. In ducks, however, the functional role of IRF1 remains unknown. Here, we identified duck IRF1 (duIRF1) is essential to counteract viral invasion. duIRF1 is most abundant in duck spleen, and virus infection or poly(I:C) stimulation significantly induced duIRF1 expression in vivo and in vitro. Overexpression of duRF1 induces the expression of type I IFN-β, type III IFN-λ, and interferon stimulated genes (ISGs) in duck embryo fibroblasts (DEFs), initiating cells resistant to avian viruses infection. More importantly, we found duIRF1 interacts with duck myeloid differentiation factor 88 (duMyD88) to activate duck IFN-β, different from IRF3 and IRF7, which involve in IFN expression through the retinoic acid–inducible gene I (RIG-I)–like receptor pathway in mammals. Together, these results indicate that duIRF1 effectively inhibits viral replication through the induction of IFN and antiviral ISGs. This will help with understanding the role of duIRF1 mediated antiviral responses by innate immune mechanisms.