Obesity and related metabolic diseases associated with chronic low‐grade inflammation greatly compromise human health. Previous observations on the roles of interferon regulatory factors (IRFs) in the regulation of metabolism prompted investigation of the involvement of a key family member, IRF3, in metabolic disorders. IRF3 expression in the liver is decreased in animals with diet‐induced and genetic obesity. The global knockout (KO) of IRF3 significantly promotes chronic high‐fat diet (HFD)‐induced hepatic insulin resistance and steatosis; in contrast, adenoviral‐mediated hepatic IRF3 overexpression preserves glucose and lipid homeostasis. Furthermore, systemic and hepatic inflammation, which is increased in IRF3 KO mice, is attenuated by the overexpression of hepatic IRF3. Importantly, inhibitor of nuclear factor kappa B kinase beta subunit / nuclear factor kappa B (IKKβ/NF‐κB) signaling is repressed by IRF3, and hepatic overexpression of the inhibitor of κB‐α (IκBα) reverses HFD‐induced insulin resistance and steatosis in IRF3 KO mice. Mechanistically, IRF3 interacts with the kinase domain of IKKβ in the cytoplasm and inhibits its downstream signaling. Moreover, deletion of the region of IRF3 responsible for the IRF3/IKKβ interaction inhibits the capacity of IRF3 to preserve glucose and lipid homeostasis. Conclusion: IRF3 interacts with IKKβ in the cytoplasm to inhibit IKKβ/NF‐κB signaling, thus alleviating hepatic inflammation, insulin resistance, and hepatic steatosis. (Hepatology 2014;59:870–885)