For the nervous system to function properly, mature neurons must have a stable dendritic architecture. Mature neurons still possess the capacity for structural plasticity, which is necessary to facilitate adaptive processes such as memory formation. What molecular and cellular mechanisms regulate this fine balance between dendritic structural stabilization and plasticity is unknown. Aberrant connectivity is the consequence of atrophy or maladaptive plasticity, which fails to preserve the ideal dendritic structure and is linked to a number of neurological disorders. The upkeep of mature dendritic trees depends on vascular endothelial growth factor D (VEGFD). Here, we describe the effects of VEGFD on the neuronal cytoskeleton and show that it influences the actin cortex and decreases microtubule dynamics to affect dendrite stabilization. Moreover, we discovered that VEGFD is downregulated during structural plasticity induced by synaptic activity. Our research demonstrated that VEGFD opposes structural changes by adversely influencing dendritic growth in both cultured hippocampal neurons and in vivo in the adult mouse hippocampus. A phosphoproteomic screening revealed multiple cytoskeleton regulatory proteins that are influenced by VEGFD. Among the actin cortex-associated proteins, we found that VEGFD induces dephosphorylation of ezrin at tyrosine 478 via activation of the striatal-enriched protein tyrosine phosphatase (STEP). Expression of a phospho-deficient mutant ezrin both in vitro and in vivo reduced the activity-triggered structural plasticity of dendrites. Thus, VEGFD functions as a molecular brake on structural remodeling, regulating the balance between dendritic stabilization and plasticity.