Viral infection or TLR3 engagement causes activation of the transcription factors IRF‐3 and NF‐κB, which collaborate to induce transcription of type I IFN genes. IKKε and TBK1 are two IKK‐related kinases critically involved in virus‐ and TLR3‐triggered activation of IRF‐3. We identified a protein termed SIKE (for Suppressor of IKKε) that interacts with IKKε and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Overexpression of SIKE disrupted the interactions of IKKε or TBK1 with TRIF, RIG‐I and IRF‐3, components in virus‐ and TLR3‐triggered IRF‐3 activation pathways, but did not disrupt the interactions of TRIF with TRAF6 and RIP, components in TLR3‐triggered NF‐κB activation pathway. Consistently, overexpression of SIKE inhibited virus‐ and TLR3‐triggered interferon‐stimulated response elements (ISRE) but not NF‐κB activation. Knockdown of SIKE potentiated virus‐ and TLR3‐triggered ISRE but not NF‐κB activation. Moreover, overexpression of SIKE inhibited IKKε‐ and TBK1‐mediated antiviral response. These findings suggest that SIKE is a physiological suppressor of IKKε and TBK1 and plays an inhibitory role in virus‐ and TLR3‐triggered IRF‐3 but not NF‐κB activation pathways.