The host recognition of intracellular viral RNA and subsequent induction of cytokine signalling is tightly regulated at the cellular level and is a target for manipulation by viruses and therapeutics alike. We previously performed a functional genomics screen that identified an uncharacterised human protein (designated C6) that promotes infection by the highly pathogenic RNA viruses Hendra and Nipah. Here we characterise C6 as a novel evolutionarily-conserved inhibitor of the innate antiviral response that also promotes infection by a range of RNA viruses from the order Mononegavirales. C6 suppresses the transcription of interferons (IFN)-α/β and the pro-inflammatory tumor necrosis factor (TNF)-α in response to the double-stranded RNA mimic poly(I:C). However, it does this without impairing upstream transcription factor (eg IRF3, NFκB) activation or nuclear translocation, and also doesn’t induce degradation of IRF3 or NFκB as has been reported for numerous inhibitors of antiviral signalling. Instead, C6 interacts with IRF3 and inhibits its binding to consensus sites in the IFN-β promoter, thus regulating cytokine transcription from within the nucleus. Deletion mapping experiments have also identified two conserved domains in the N-terminal region of C6 which are required for the inhibition of IRF3 DNA binding and downstream induction of cytokine transcription. Thus we hypothesise that C6 represents a novel mechanism for nuclear inhibition of cytokine expression which has implications for antiviral immunity, autoimmune disorders and cancer.