Collectively, this study demonstrates the novel pharmacological effect that acacetin is effective in protecting against vascular endothelial cells injury induced by hyperglycemia by preserving mitochondrial function via Sirt1-mediated activation of Sirt3/AMPK/PGC-1α signaling molecules, thereby attenuating diabetes-accelerated atherosclerosis. Here, PPARGC1A is linked to atherosclerosis.