A hallmark event in the development of atherosclerotic plaque is the accumulation of lipid-laden macrophages in the subendothelial layers of affected blood vessels. Macrophages are key players in all stages of atherogenesis, including plaque initiation, growth, and rupture, as well as healing of ruptured plaques. In this context, macrophages are the principal innate immune cells that modulate atherogenesis by engaging in various processes, such as inflammation, extracellular matrix degradation, phagocytosis, and efferocytosis. In the current study, Kruppel-like transcription factor 6 (KLF6) deficiency attenuated proinflammatory gene expression in macrophages and experimentally induced atherosclerotic plaque development. In vivo studies showed that myeloid-KLF6 deficiency on Apoe-null background significantly curtailed high-fat/high-cholesterol diet-induced atherosclerotic lesion formation and macrophage abundance in atherosclerotic plaques. Integrated transcriptomics and Gene Set Enrichment Analysis showed that KLF6 deficiency significantly curtailed a large number of tumor necrosis factor (TNF)-induced gene targets, TNF-induced interferon-γ response, interferon-α response, and inflammatory response signaling in macrophages. At the molecular level, KLF6 promoted interferon regulatory factor 1 (IRF1) signaling to enhance TNF-induced proinflammatory gene expression in macrophages. Collectively, study results show that KLF6 promoted proinflammatory gene expression in macrophages and enhanced experimentally induced atherosclerotic plaque formation in vivo.