Aim To investigate whether p38MAPK signaling pathway is involved in the protective mechanism of glucagon like peptide-1 (GLP-1) on endothelial cell damage induced by advanced glycation endproducts (AGE). Methods The experiment was divided into control group, AGE group, GLP-1 group, AGE+GLP-1 group, AGE+SB203580 group, AGE+GLP-1+SB203580 group, AGE+GLP-1+L-NAME group. Expression of p-p38MAPK/p38MAPK, phospho endothelial nitric oxide synthase/endothelial nitric oxide synthase (p-eNOS/eNOS) protein were examined by Western blot. Nitric oxide (NO) generation was detected by NO detection kit. Reactive oxygen species (ROS) generation was examined by fluorescent probe technique. The apoptosis rate was tested by Annexin V/PI flow cytometry. Results Compared with AGE group, GLP-1 inhibited the expression of p-p38MAPK protein(P=0.000). Compared with control group, after adding GLP-1 or p38MAPK inhibitor (SB203580), the expression of eNOS protein inhibited and ROS generation induced by AGE was significantly increased(P=0.004)or decreased(P=0.000). After adding GLP-1, the increased apoptosis rate induced by AGE was inhibited significantly(P=0.000). While after adding L-NAME, the anti-apoptosis effect was significantly weakened(P=0.002). After adding GLP-1, NO generation increased significantly(P=0.000) compared with AGE group. While after adding L-NAME, NO generation decreased significantly(P=0.011). Conclusion GLP-1 can inhibit the oxidative damage of vascular endothelial cells by inhibiting the activation of p38MAPK signaling pathway, and increase the expression of eNOS protein to increase NO generation and antagonize apoptosis induced by AGE.