Little is known about the response of non-model invertebrates, such as oysters, to viral infection. The vertebrate innate immune system detects virus-derived nucleic acids to trigger the type I interferon (IFN)-pathway, leading to the transcription of hundreds of IFN-stimulated genes (ISGs) that exert antiviral functions. Invertebrates were thought to lack the IFN-pathway based on the absence of IFN or ISGs encoded in model-invertebrate genomes. However, the oyster genome encodes many ISGs, including the well-described antiviral protein, viperin. In this study, we characterise oyster-viperin and show it localises to caveolin-1 and inhibits Dengue virus replication in a heterologous model. In a second set of experiments, we provide evidence that the hemolymph from poly(I:C)-injected oysters contains a heat-stable, protease-susceptible factor that induces hemocyte transcription of viperin mRNA in conjunction with upregulation of IFN-regulatory factor. Collectively, these results support the concept that oysters have antiviral systems that are homologous to the vertebrate IFN-pathway.