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Summary Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2 , enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2 −/− mice and OASL -deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway. cGAS was necessary for the reduced DNA virus replication observed in OASL -deficient cells. OASL directly and specifically bound to cGAS independently of double-stranded DNA, resulting in a non-competitive inhibition of the second messenger cyclic GMP-AMP production. Our findings define distinct mechanisms by which OASL differentially regulates host IFN responses during RNA and DNA virus infection and identify OASL as a negative-feedback regulator of cGAS. Graphical Abstract Highlights • Loss of human OASL and mouse Oasl2 inhibits DNA virus infection • OASL and Oasl2 inhibit cGAS-mediated IFN induction • OASL specifically binds to cGAS to inhibit cGAS enzyme activity • OASL binds to cGAS independently of double-stranded DNA The interferon (IFN)-stimulated gene OASL enhances RNA-sensor RIG-I-mediated IFN induction to inhibit RNA virus replication. In contrast, Ghosh et al. show that during DNA virus infection, OASL binds to the DNA sensor cGAS to inhibit IFN induction and enhance DNA virus replication. These findings highlight the distinct regulation of IFN induction by OASL during RNA and DNA virus infection. [ABSTRACT FROM AUTHOR]