In this study, we reported for the first time that SerpinA5 can play a novel antiviral function as an IFN-stimulated gene, and we also provided evidence that SerpinA5 can upregulate the phosphorylation of STAT1, and thus promote the formation of a STAT1/STAT2 complex and its nuclear translocation to effectively activate the transcription of IFN-related signaling pathways to impair viral infections. Here, STAT2 is linked to viral infectious disease.