Significance Macrophages play a crucial role in chronic inflammatory diseases, such as nonalcoholic steatohepatitis (NASH) and inflammatory bowel disease, but how the proinflammatory function of macrophages is controlled is not well understood. In this work, we identified TBK1 as a pivotal anti-inflammatory factor in macrophages that restricts inflammation in different disease models. Myeloid cell–specific TBK1 deficiency causes spontaneous development of metabolic disorders in aged mice and exacerbates high-fat diet–induced fatty liver disease with NASH-like symptoms. The Tbk1 -MKO mice are also hypersensitive to experimental colitis. We obtained genetic evidence that TBK1 is crucial for controlling proinflammatory signaling pathway in macrophages. These findings establish TBK1 as a pivotal anti-inflammatory factor and a potential therapeutic target for the treatment of inflammatory diseases.