The immediate-early protein IE180 of (PRV) is a multifunctional regulator of viral and host gene expression. However, its role in modulating antiviral immune responses remains poorly understood. Here, we demonstrate that IE180 overexpression significantly inhibits PRV and replication in Hep2 and A549 cells, respectively. Mechanistically, IE180 activates the type I interferon (IFN-I) pathway by enhancing IFN-β promoter activity and IFN transcription, leading to upregulated expression of interferon-stimulated genes (). Notably, IE180 failed to suppress PRV or H1N1 replication in Vero cells, which lack functional IFN-I signaling, confirming the dependence of its antiviral function on the IFN-I pathway. Domain mapping revealed that the ICP4-Like2 domain of IE180 is critical for IFN-β activation and antiviral activity. These findings establish IE180 as a novel viral immunomodulator that activates host innate immunity to restrict viral replication, providing insights into PRV-host interactions and potential therapeutic strategies.