Epilepsy is a neurological disorder characterized by recurrent seizures that arise from abnormal electrical activity in the brain. Voltage-gated sodium channels (NaVs), responsible for the initiation and propagation of action potentials in neurons, play a critical role in the pathogenesis of epilepsy. This study sought to discover potential anticonvulsant compounds that interact with NaVs, specifically, the brain subtype hNaV1.2. A ligand-based QSAR model and a docking model were constructed, validated, and applied in a parallel virtual screening over the DrugBank database. Montelukast, Novobiocin, and Cinnarizine were selected for in vitro testing, using the patch-clamp technique, and all of them proved to inhibit hNaV1.2 channels heterologously expressed in HEK293 cells. Two hits were evaluated in the GASH/Sal model of audiogenic seizures and demonstrated promising activity, reducing the severity of sound-induced seizures at the doses tested. The combination of ligand- and structure-based models presents a valuable approach for identifying potential NaV inhibitors. These findings may provide a basis for further research into the development of new antiseizure drugs for the treatment of epilepsy.