Angiogenesis is a crucial process in ischemia diseases like coronary heart disease, stroke and wound healing. Panasenoside (PSS) is a flavonoid glycoside ioslated from Chinese Materia Medica GINSENG RADIX ET RHIZOMA which has been demonstrated with multiple biological activities. However, the pharmacological activity of PSS and the underlying mechanism are still unclear. We found that PSS promoted sub-intestinal vessel plexus (SIVs) growth in zebrafish. PSS ameliorated vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor II (VRI)-induced deficiency of intersegmental vessels (ISVs) in a concentration dependent manner by downregulation of mRNA expression of VEGF receptors, including Kdr/VEGFR-2 ( kdr), VEGFR-1 ( flt1), and Kdr-like/VEGFR-2 (kdrl) , and up-regulation of VEGF ( vegfaa ). The angiogenesis effect of PSS on VRI-induced ISVs deficiency was suppressed by PI3K, AKT, MEK, ERK, P38, Sirtuin 1 (SIRT1), Nuclear factor erythroid-2-related factor 2 (NRF2) and Nicotinamide N-methyl transferase (NNMT) inhibitors. Activation of NRF2, SIRT1 and MNA significantly restored VRI-induced ISVs insufficiency. In addition, PSS protected against VRI-induced tube formation deficiency in human umbilical vascular endothelial cells (HUVECs). SIRT1, NRF2 and NNMT inhibitors or siRNA eliminated PSS promoting vascular endothelial cell tube formation. PSS also prevented SIRT1, NRF2 and NNMT inhibitors-induced vascular endothelial cell senescence. Furthermore, PSS upregulated the protein expression level of SIRT1 and downregulated its downstreams P53 and PGC-1α in HUVECs with high potence of activating SIRT1 by binding with its active domine. In conclusion, PSS presented pro-angiogenesis effect by mitigating vascular endothelial cell ageing and the underlying mechanisms were involved in the PI3K/AKT/MAPKs, SIRT1/NRF2 and NNMT/MNA signaling pathway with SIRT1 acting as a key regulator. We identified the pro-angiogenesis and anti-vascular endothelial cell ageing effects of PSS for the first time, and PSS is a promising drug candidate for treating vascular deficiency associated diseases.