Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial?anti-viral?activity?against PRV as well as a range of?DNA?and RNA viruses. We further demonstrated that?BRD4?inhibition?boosted a robust?innate?immune?response.?BRD4?inhibition?also de-compacted chromatin structure and induced the?DNA?damage response, thereby triggering the activation of cGAS-mediated?innate?immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of?BRD4?inhibition?on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which?BRD4?inhibition?restrains viral infection and points to its potent therapeutic value for viral infectious diseases.