The persistence of drug-resistant epilepsy indicates the need for new therapeutic interventions against novel targets with reduced side effects. One such approach is modifying underlying pathophysiological mechanisms of synaptic plasticity, contributing to the reduced seizure threshold. We show that the administration of Urolithin-A (UA), a small molecule of natural origin, mitigates behavioral and synaptic dysfunctions under chemically and genetically induced epileptic conditions in Drosophila. Additionally, chronic treatment with UA attenuates the altered basal synaptic transmission and single-cell post-synaptic currents, curtailing the deleterious consequences of PTZ-induced chronic kindling of mice. However, UA exerts no seizure-suppressive effects in in-vitro epileptic conditions, implying the absence of acute symptomatic anti-epileptic effects. Here, we identify the direct interactor of UA as the complex of tubulin dimer and VDAC1 through affinity-purification with synthesized UA-attached beads and transcriptomics studies. Finally, neuron specific VDAC1 knockdown in Drosophila mimics UA supplementation effects. VDAC1 inhibition through UA offers new hope as a distinct neuroprotective therapeutic intervention for refractory epilepsy.