Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evidence supports a working mechanism through voltage-gated sodium (Na_v) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Na_v1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNa_v1.1. Subsequent structure–activity relationship experiments with related N-benzyl triazole compounds on four brain hNa_v channel isoforms revealed a novel drug variant that (1) shifts hNa_v1.1 opening to more depolarized voltages without further alterations in the gating properties of hNa_v1.1, hNa_v1.2, hNa_v1.3, and hNa_v1.6; (2) increases the threshold to action potential initiation in hippocampal neurons; and (3) greatly reduces the frequency of seizures in three animal models. Altogether, our results provide novel molecular insights into the rational development of Na_v channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Na_v channel isoforms while limiting adverse effects.