Glucocorticoids dramatically inhibit cytokine and chemokine production. They act through the glucocorticoid receptor (GR), a ligand‐dependent transcription factor that binds to and represses activities of other DNA‐bound regulators, activator protein 1 and nuclear factor κB, utilizing a p160 GRIP1 as a corepressor. A yeast two‐hybrid screen with the GRIP1 corepression domain (RD) yielded interferon (IFN) regulatory factor (IRF)3—a downstream effector of Toll‐like receptors (TLR) 3/4 and an essential activator of several IFN and chemokine genes. We defined the GRIP1:IRF3 interface and showed that endogenous GRIP1 and IRF3 interact in mammalian cells. Interestingly, GR and IRF3 competed for GRIP1 binding; GR activation or GRIP1 knockdown in macrophages blocked whereas GRIP1 overexpression rescued IRF3‐dependent gene expression. GR interference persisted in MyD88‐ and IFNA receptor‐deficient mice, suggesting a specific disruption of TLR3–IRF3 pathway, not of autocrine IFN signaling. Finally, IRF3‐stimulated response elements were necessary and sufficient for TLR3‐dependent induction and glucocorticoid inhibition. Thus, GRIP1 plays a cofactor role in innate immunity. Competition with GR for GRIP1 antagonizes IRF3‐mediated transcription, identifying the GRIP1:IRF3 interaction as a novel target for glucocorticoid immunosuppression.