Post-stroke angiogenesis improves structural and functional recovery, outlining the promises of pro-angiogenic therapies. Unfortunately, vascular endothelial growth factor (VEGF)-A-mediated angiogenesis resulted in mitigated outcomes, as it significantly increases the risk of exacerbating injury via destabilization of the cerebrovascular network. VEGF-E, a non-mammalian VEGF-A homolog, has been reported to promote stable neovascularization upon skin injuries, and thus represents an interesting safe alternative to promote post-stroke angiogenesis. C57BL6/J wildtype mice were subjected to ischemic stroke using transient middle cerebral artery occlusion (MCAo), and recombinant VEGF-E was intranasally delivered throughout the subacute phase. Our results indicate that VEGF-E reduces neuronal loss and improves motor recovery after stroke. VEGF-E attenuates cerebrovascular permeability at the injury site and increases the density of mature CD31+ microvessels. Furthermore, we show that VEGF-E reduces the events of microvascular stalls and improves brain endothelial cell coverage by perivascular cells, required for cerebrovascular stability. VEGF-E increases the density of angiogenic active CD105+ microvessels, while improving the recruitment of CD13+ pericytes, outlining synergistic effects on microvessel formation and stabilization. Using cell-based assays, we demonstrate that VEGF-E activates key pro-survival pathways in brain endothelial cells exposed to ischemia/reperfusion-like conditions, namely extracellular signal-regulated kinase (ERK)1/2 and P38 mitogen-activated protein kinase (MAPK) while preserving the tight junctions. Importantly, we report that the secretome of VEGF-stimulated brain endothelial cells improves perivascular cell migration that is required to mediate the interaction with endothelial cells. Our study indicates that VEGF-E promotes a stable neovascularization after ischemic stroke, paving the way to develop new strategies for therapeutic angiogenesis.