Abstract: Endothelial dysfunction has been observed in diabetes mellitus, which is related to hyperglycemia. Previous studies have shown that incubation of human umbilical vein endothelial cells (HUVECs) in high glucose causes a significant increase in apoptosis, possibly related to an increase in oxidative stress. The present study aims at investigating the protective effects of Clinopodium chinense extract (CCE) on high glucose–induced apoptosis and the underlying mechanisms. We show that treatment of CCE significantly increased cell viability and the activity of superoxide dismutase, reduced oxidative stress, and protected HUVECs against apoptosis induced by high glucose. Furthermore, our results demonstrate that the antiapoptotic effect of CCE was associated with the reduction of Bax expression and caspase-3 activity and the elevation of Bcl-2 expression. The decrease in caspase-3 activity and caused by CCE were blocked by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase, the upstream kinase of Akt. Moreover, treatment of CCE on HUVECs resulted in dose-dependenent phosphorylation of Akt and inhibited the activation of NF-κB. Taken together, our results indicate that CCE could play an important role in protecting endothelial cell by inhibiting oxidative stress and modulating cell apoptosis signaling via the pAkt/NF-κB/Bax/Bcl-2/caspase-3 pathway, suggesting that it might be useful for the treatment of endothelial dysfunction–associated diseases such as vascular complications of diabetes mellitus.