Avian influenza virus is a globally prevalent pathogen in poultry populations, causing severe economic losses to the poultry industry worldwide. In the present study, we demonstrate that miR-449c generates two mature isoforms including miR-449c-3p and miR-449c-5p and exerts potent inhibitory effects on avian influenza virus replication. Mechanistically, we identified distinct antiviral pathways mediated by these two mature miR-449c isoforms. MiR-449c-5p enhances type I interferon responses by targeting the Suppressor of cytokine signaling 3 (SOCS3), thereby suppressing avian influenza virus replication. Meanwhile, miR-449c-3p inhibits viral replication through direct targeting and binding to the PB1 gene of avian influenza virus. Furthermore, we characterized the role of avian SOCS3 in avian influenza virus infection. We found that SOCS3 promotes avian influenza virus replication by dampening interferon responses, which is achieved through its interaction with and subsequent degradation of interferon regulatory factor 7 (IRF7), a key transcription factor that drives the expression of interferon stimulated genes (ISGs). Collectively, our findings uncover a novel dual-mode antiviral mechanism orchestrated by avian miR-449c, providing a theoretical foundation for the development of novel antiviral strategies.