Senescent endothelial cells (ECs) could impair the integrity of the blood vessel endothelium, leading to vascular aging and a series of diseases, such as atherosclerosis, diabetes. Preventing or mitigating EC senescence might serve as a promising therapeutic paradigm for these diseases. Recent studies showed that small extracellular vesicles (sEV) have the potential to transfer bioactive molecules into recipient cells and induce phenotypic changes. Since mesenchymal stem cells (MSCs) have long been postulated as an important source cell in regenerative medicine, herein we investigated the role and mechanism of MSC-derived sEV (MSC-sEV) on EC senescence. In vitro results showed that MSC-sEV reduced senescent biomarkers, decreased senescence-associated secretory phenotype (SASP), rescued angiogenesis, migration and other dysfunctions in senescent EC induced by oxidative stress. In the In vivo natural aging and type-2 diabetes mouse wound-healing models (both of which have senescent ECs), MSC-sEV promoted wound closure and new blood vessel formation. Mechanically, miRNA microarray showed that miR-146a was highly expressed in MSC-sEV and also upregulated in EC after MSC-sEV treatment. miR-146a inhibitors abolished the stimulatory effects of MSC-sEV on senescence. Moreover, we found miR-146a could suppress Src phosphorylation and downstream targets VE-cadherin and Caveolin-1. Collectively, our data indicate that MSC-sEV mitigated endothelial cell senescence and stimulate angiogenesis through miR-146a/Src.