DNA damage response (DDR) is a sophisticated cellular network that detects and repairs DNA breaks. Viruses are known to activate the DDR and usurp certain DDR components to facilitate replication. Intriguingly, viruses also inhibit several DDR proteins, suggesting that this cellular network has both proviral and antiviral features, with the nature of the latter still poorly understood. In this study we show that irradiation of primary murine macrophages was associated with enhanced expression of several antiviral interferon (IFN)-stimulated genes (ISGs). ISG induction in irradiated macrophages was dependent on type I IFN signaling, a functional DNA damage sensor complex, and ataxia-telangiectasia mutated kinase. Furthermore, IFN regulatory factor 1 was also required for the optimal expression of antiviral ISGs in irradiated macrophages. Importantly, DDR-mediated activation of type I IFN signaling contributed to increased resistance to mouse gammaherpesvirus 68 replication, suggesting that the coordinate regulation of DDR and type I IFN signaling may have evolved as a component of the innate immune response to virus infections.