Stachydrine is a main active component of Leonurus japonicus (Chinese motherwort), which has traditionally been used to promote postpartum recovery and alleviate myocardial and cerebral ischemic injuries due to its pro-angiogenic effect. Our prior study demonstrated that stachydrine increased angiogenesis in zebrafish embryos, but its pro-angiogenic effect and underlying mechanisms on human umbilical vein endothelial cells (HUVECs) remain largely unknown. In the present study, we further investigated the role of stachydrine in sunitinib-injured HUVECs and its potential molecular mechanisms. The results showed that stachydrine exhibited a protective effect on sunitinib-injured HUVECs and significantly promoted their proliferation, migration, and tube formation, all central events of angiogenesis. In addition, stachydrine inhibited apoptosis and ROS production in sunitinib-injured HUVECs. Furthermore, our findings illustrated for the first time that stachydrine’s molecular mechanisms for promoting angiogenesis might correlate with activation of the VEGFR2/MEK/ERK and inhibition of the mitochondrial-mediated apoptosis signaling pathway.