Worldwide, epilepsy is the second most prevalent neurological disorder. Disappointingly, various adverse effects are being observed with currently used antiepileptic drugs. Nanomedicine represents an effective strategy to overcome these limitations with a better central drug delivery. Hence, our work aimed to unravel the antiepileptic efficacy of rutin (Rut) loaded with selenium nanoparticles (SeNPs) against pentylenetetrazole (PTZ)-challenged mice. Ten days before PTZ (60 mg·kg −1 ) intraperitoneal injection, mice were orally administered Rut (100 mg·kg −1 ), sodium selenite (0.5 mg·kg −1 ), SeNPs (100 mg·kg −1 ), or sodium valproate (reference drug, 200 mg·kg −1 ). Remarkably, administration of Rut-loaded SeNPs (Rut-SeNPs) to epileptic mice markedly increased the latency time and decreased the severity and duration of seizures. Remarkable increases were also noticed in acetylcholinesterase, brain-derived neurotrophic factor, dopamine, and norepinephrine levels in epileptic mice treated with Rut-SeNPs. Furthermore, Rut-SeNPs boosted the cellular antioxidant defense by increasing superoxide dismutase, catalase, GSH, Nrf2, and HO-1, along with decreased malondialdehyde and nitric oxide levels. In addition, the nanotherapy successfully mitigated the inflammatory mediators (tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, and nuclear factor kappa B) in mice hippocampus. Rut-SeNPs antagonized neuronal apoptosis by decreasing Bax and caspase-3 and increasing the levels of Bcl-2. Conclusively, the present work suggests Rut-loaded SeNPs as an effective antiepileptic therapy through correction of disturbed neurotransmitters, oxidative status, neuroinflammation, and apoptosis.