Neuritogenesis, a complex process of sprouting of neurites, plays vital role in structural and functional restoration of cerebral ischemia injured neuronal tissue. Practically, there is no effective long-term treatment strategy for cerebral ischemia in clinical practice till date due to several limitations of conventional therapies, facilitating the urgency to develop new alternative therapeutic approaches. Herein, for the first time we report that pro-angiogenic nanomaterial, zinc oxide nanoflowers (ZONF) exhibit neuritogenic activity by elevating mRNA expression of different neurotrophins, following PI3K/Akt-MAPK/ERK signaling pathways. Further, ZONF administration to global cerebral ischemia induced Fischer rats show improved neurobehaviour and enhanced synaptic plasticity of neurons via upregulation of Neurabin-2 and NT-3, revealing their neuroprotective activity. This study offers the basis for exploitation of angio-neural cross talk of other pro-angiogenic nano/bio-materials for future advancement of alternative treatment strategies for cerebral ischemia, where neuritogenesis and neural repair are highly critical.