The aim of this study was to investigate the effect of metformin on endothelial progenitor cells (EPCs) angiogenesis under physiology condition and to explore the possible mechanisms. Methods: EPCs were treated with metformin and angiogenesis of EPCs were evaluated by capillary tube formation assay in Matrigel. Moreover, we also assessed AMPK-mTOR-autophagy pathway to explore the possible mechanisms. Results: Metformin treatment could significantly down-regulate metal matrix Proteinase 2 (MMP2), MMP9 and urokinase-type plasminogen activator (uPA) expression, and subsequently decrease angiogenesis of EPCs. Increased levels of phospho-AMPK and LC3II expression, as well as decreased phospho-mTOR, contribute to this phenomenon. Down-regulated autophagy by autophagy protein 5 siRNA could reverse the effect exerted by metformin. Conclusions: Our results here showed that metformin could inhibit EPCs angiogenesis through inhibiting the expression of MMP2, MMP9 and uPA via AMPK-mTOR-autophagy pathway.