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In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNβ. This binding leads to the sequestration of IFNβ mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown. [Display omitted] • Human and mouse OAS1 protect against WNV through a non-canonical mechanism • OAS1 binds multiple cellular mRNAs through its unique endomembrane localization • OAS1 binds to the ARE region of IFN mRNA, which prolongs half-life and expression • Increased IFN expression by OAS1 leads to WNV inhibition via IFNAR signaling How cells induce the production of antiviral molecules while shutting down protein translation to limit viral replication remains unclear. Here, Harioudh et al. show a non-canonical function for the interferon-induced antiviral protein, OAS1, which sequesters and protects Ifnb mRNA from degradation to sustain innate antiviral protection against West Nile virus. [ABSTRACT FROM AUTHOR]