STING (STimulator of INterferon Genes protein) is a critical endoplasmic reticulum adaptor protein that facilitates innate immune responses. Besides from regulating protective immune responses to pathogens, STING also contributes to autoimmune and inflammatory syndromes. Post-transcriptional modifications of STING have been described as key regulators governing STING function, however STING transcriptional regulation is not fully elucidated yet. Here, we report that Nrf2 transcription factor, a critical regulator of redox homeostasis, interferes with the induction of the antiviral response by blocking STING transcription through binding to its promoter. Comparison of antiviral gene expression profile by RNA-seq analysis of wild-type (WT) and Nrf2 mutant macrophages showed an increase in the interferon-stimulated gene response in absence of functional Nrf2. The same basal increased antiviral profile was also observed in the spleen of Nrf2 knock-out (KO) mice. Silencing Nrf2 in human epithelial cells that display constitutive dominant hyperactivation of Nrf2 increased STING mRNA and protein levels. Conversely, silencing the Nrf2 repressor Keap1 using siRNA drastically impaired STING expression in human fibroblasts. Enhanced Nrf2 signaling through either genetic inhibition of Keap1 or sulforaphane stimulation abolished STING-dependent antiviral signaling in human cells. Mechanistically, Chromatin immunoprecipitation (ChIP)-qPCR analyses showed that Nrf2 suppressed STING transcription by binding to the proximity of the Tmem173 gene. Finally, using a murine vaginal herpes infection model, we showed that Nrf2 critically controlled early innate immune responses to herpes simplex virus-2. Indeed, Nrf2 KO mice exhibited decreased vaginal viral titers that were associated with higher levels of typ I IFN release in vaginal washes. Subsequently, Nrf2 KO mice developed significantly lower disease scores and higher survival rates compared to WT animals. Collectively, these data identify Nrf2 as an upstream regulator of the antiviral response through the modulation of STING expression and establish the molecular basis for Nrf2-mediated anti-inflammatory therapeutic approaches.