Our purpose was to study the effect of hyperglycemia on macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling and its correlation with coronary atherosclerosis. A total of 135 patients with coronary heart disease (CHD) were divided into a stable CHD (SCHD) group (n = 30) and an acute myocardial infarction (AMI) group (n = 105) [nondiabetes mellitus (non-DM)-AMI, n = 60; DM-AMI, n = 45] from January to September 2020. The SYNTAX score and metabolic and inflammatory markers were quantified and compared. THP-1 cell studies and an animal study of coronary intimal hyperplasia were also carried out. We found that the DM-AMI group showed a higher SYNTAX score than the non-DM-AMI group (P < .05). The DM-AMI group showed the highest expression levels of TANK-binding kinase 1 (TBK1), hypoxia-inducible factor 1α (HIF-1α), and interleukin (IL)-17 and the lowest expression level of IL-10, followed by the non-DM-AMI group and the SCHD group (P < .05). THP-1 cell studies showed that BAY87-2243 (a HIF-1α inhibitor) reversed the increase in IL-17 and decrease in IL-10 expression induced by hyperglycemia. Amlexanox (a TBK1 inhibitor) reversed the increase in HIF-1α expression induced by hyperglycemia. Amlexanox treatment resulted in lower coronary artery intimal hyperplasia and a larger lumen area in a diabetic swine model. We conclude that hyperglycemia might aggravate the complexity of coronary atherosclerosis through activation of TBK1-HIF-1α-mediated IL-17/IL-10 signaling. Thus, TBK1 may be a novel drug therapy target for CHD complicated with DM. © 2021 Federation of American Societies for Experimental Biology.