Spinal cord injury (SCI) leads to local vascular disruption and progressive ischemia, which contribute to secondary degeneration. Enhancing angiogenesis through the induction of vascular endothelial growth factor (VEGF)-A expression therefore constitutes an attractive therapeutic approach. Moreover, emerging evidence suggests that VEGF-A may also exhibit neurotrophic, neuroprotective, and neuroproliferative effects. Building on this previous work, we seek to examine the potential therapeutic benefits of an engineered zinc finger protein (ZFP) transcription factor designed to activate expression of all isoforms of endogenous VEGF-A (ZFP-VEGF). Administration of ZFP-VEGF resulted in increased VEGF-A mRNA and protein levels, an attenuation of axonal degradation, a significant increase in vascularity and decreased levels of apoptosis. Furthermore, ZFP-VEGF treated animals showed significant improvements in tissue preservation and neurobehavioural outcomes. These data suggest that activation of VEGF-A via the administration of an engineered ZFP transcription factor holds promise as a therapy for SCI and potentially other forms of neurotrauma.