Atherosclerosis drives cardiovascular morbidity in diabetes, with endothelial-to-mesenchymal transition (EndMT) as a key contributor. Whereas epigenetic regulators are increasingly implicated in atherosclerotic progression, the specific role of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, in EndMT in diabetes-associated atherosclerosis remains unclear. We show that EZH2-mediated H3K27 (histone H3 at lysine-27) trimethylation is elevated in carotid plaques from patients with diabetes and in the aortic endothelium of diabetic Apoe-/- mice. Pharmacologic EZH2 inhibition with GSK-126 attenuated EndMT and reduced atherosclerotic burden in diabetic mice. In human aortic endothelial cells exposed to high glucose/tumor necrosis factor-α or serum from patients with coronary artery disease, EZH2 blockade via GSK-126 or short hairpin RNA suppressed EndMT and reversed transcriptional programs assessed by RNA sequencing, including COL4A1 and NR2F2. These findings identify EZH2 as a driver of EndMT in diabetes-associated atherosclerosis and highlight EZH2 inhibition as a potential therapeutic strategy to limit vascular pathology.