Sirt3 is a central regulator of mitochondrial adaptation in health and disease. Our aim was to investigate the potential roles of Sirt3 in ox-LDL-treated endothelial cells. Short-term ox-LDL treatment of primary human umbilical vein endothelial cells (HUVECs) triggered autophagy, whereas long-term ox-LDL treatment resulted in apoptosis. Sirt3 expression consistently rose after short-term ox-LDL treatment and declined after long-term treatment of HUVECs. Pre-treatment with the Sirt3 activator resveratrol or Sirt3 overexpression enhanced autophagy and postponed HUVECs’ apoptosis under long-term ox-LDL treatment. In contrast, Sirt3 knockdown by siRNAs dramatically increased apoptosis of oxLDL-treated HUVECs. Resveratrol enhanced Sirt3 activity, augmenting MnSOD/SOD2 enzyme activity and expression by upregulation of FOXO3 binding and transcriptional activity at the MnSOD/SOD2 promoter. We conclude that moderate autophagy is a protective mechanism against oxidative stress over a short period. Resveratrol attenuates ox-LDL-induced endothelial cell apoptosis partially by elevating autophagy, which depends on Sirt3 participation.