Nitrosodiethylamine (NDEA) is a potent oxidant induces neurodegeneration via (reactive oxygen species) ROS. Copper is an important metal essential for scavenging free radicals, development of central nervous system (CNS) and redox angiogenesis signaling. Vascular endothelial growth factor (VEGF) is well known as efficacious and long-term signal that stimulates angiogenesis, where its expression is copper dependent. We examined the copper protective effect against brain vascular damage initiated by NDEA. NDEA induces brain vascular wall damage, necrosis with interstitial hemorrhage and diminishes VEGF expression. Histopathological examination showing a great improvement of brain tissue in copper treated mice with significant increase in VEGF expression. Higher levels of intracellular copper can stimulate angiogenesis and exhibited a significant protection against NDEA induced brain vascular damage, confirming its ability to enhance antioxidant activity and angiogenesis initiation. Our report presents first evidence that inducible VEGF expression in brain is sensitive to copper; moreover, copper-based therapeutics represents a novel approach to reduce brain vascular damage induced by NDEA generated ROS.