Abstract 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.