Vascular endothelial growth factor (VEGF) is best known for its role in angiogenesis, but emerging evidence suggests neurotrophic and neuroprotective functions most likely connected to energy homeostasis pathways. Using high-resolution respirometry, we investigated the role of VEGF in optimizing mitochondrial oxidative phosphorylation efficiency in neuronal-like cells. Our findings indicate that VEGF enhances coupling efficiency for ATP synthesis by reducing the uncoupled respiration, a process involved in mitochondrial dysfunction and neurodegeneration, as observed in Parkinson's disease (PD). To investigate the VEGF relevance in PD, we exposed differentiated SH-SY5Y cells to MPP, a toxin inducing a PD-like phenotype. Both VEGF and a mimic peptide (VEGF) reduced MPP-induced uncoupled respiration, mitochondrial membrane potential (Δψm) collapse, and cell death. These effects were associated with Erk signaling activation, upregulation of PGC-1α genes expression and increased mitochondrial DNA. Our study underscores VEGF's multifaceted role in neuronal resilience beyond angiogenesis. Furthermore, these findings suggest that the VEGF fragment may retain key neuroprotective and neurotrophic properties supporting further exploration of its therapeutic potential.