This study employed label-free quantitative proteomics to profile the spinal cord tissue at multiple time points post-injury, aiming to uncover altered molecular pathways associated with endothelial cell dysfunction and repair. The proteomic analysis revealed lactate dehydrogenase A (LDHA) as a significantly upregulated protein at day post-injury 7 (DPI-7) and a potential regulator of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling. Pharmacological inhibition of LDHA using FX-11 exacerbated oxidative stress in endothelial cells, suppressed their proliferation, hindered angiogenesis, and aggravated neurodegeneration and microglial accumulation at the lesion epicenter. These findings suggest that LDHA acts as a metabolic regulator of endothelial cell survival and angiogenic signaling under injury conditions.