Aim To investigate the effect of Sestrin2 inhibition on apoptosis of human umbilical vein endothelial cells induced by oxidized low density lipoprotein (ox-LDL). Methods The cell injury model was induced by ox-LDL. Western blot was used to detect protein expression of Sestrin2 in human umbilical vein endothelial cells treated with different concentrations of ox-LDL at different time. Protein expression of Sestrin2 was observed by Western blot after transfection with Sestrin2 siRNA. Human umbilical vein endothelial cells were transfected with Sestrin2 siRNA, then treated with ox-LDL, cell apoptosis was detected by flow cytometry, Caspase-3 expression and JNK pathway were observed by Western blot. Results Sestrin2 expression was significantly induced after treatment at different concentrations (0,0 and 100 mg/L) of ox-LDL for 24 h. Moreover, human umbilical vein endothelial cells were incubated with 50 mg/L ox-LDL for various periods of time ranging from 0 to 48 h. The results showed a significant increase of Sestrin2 at protein levels in 24 h and 48 h, and it was the highest level in 24 h. Transfection with Sestrin2 siRNA significantly inhibited Sestrin2 expresssion. ox-LDL significantly induced cell apoptosis, transfection with Sestrin2 siRNA increased the effect. Expression of p-JNK and p-c-Jun was induced by ox-LDL, and this effect could be inhibited by SP600125. Conclusions Ox-LDL induces Sestrin2 expression through JNK/c-Jun pathway, inhibition of Sestrin2 expression significantly increases human umbilical vein endothelial cells apoptosis induced by ox-LDL.