Introduction: Endocan is a novel proteoglycan secreted from endothelium and may play a role in endothelial cell activity under diabetic conditions. In the current study, the effect of high glucose concentration (30 mmol) was evaluated on endocan level in the presence or absence of metformin in human umbilical vein endothelial cells (HUVECs). Methodsand Materials: HUVECs were incubated with 30 mmol glucose for 72 h. High glucose content, metformin (2.5 to 500 mmol), and compound C (10 mmol) effects were assessed on cell viability (using MTT assay). Endothelial cell migration was studied by scratch test. RT-PCR, ELISA, and flow cytometry analysis were used to evaluate the changes in endocan expression and protein level. Griess reaction was used to measure Nitric Oxide levels. The functional activity of endothelial cells was monitored using Dil-Ac-LDL uptake. The phosphorylation of AMPK was assessed by western blotting. Results: Cell viability and migration significantly were reduced under high glucose conditions, whereas these features were improved after treatment with metformin. Endocan transcription and protein levels were increased in diabetic endothelial cells exposed to metformin. Metformin increased NO production in HUVECs under high glucose conditions. Metformin increased LDL uptake capacity under high glucose conditions. Western blot analysis confirmed the increase of the p-AMPK/AMPK ratio in metformin-treated HUVECs. Conclusion: Based on the results it seems that metformin could improve the angiogenic potential of endothelial cells and its reduction is the main cause of the development of diabetic foot ulcers, probably by the regulation of endocan dynamics under diabetic conditions.