Background: Numerous pharmacological routes of topiramate are useful in the treatment of epilepsy and migraines. There are a lot of off-label uses for it. Because Alhagi maurorum contains phenolic and flavonoid chemicals, it has been identified as a potentially helpful medicinal plant. The study's objective was to look into the possible neuroprotective benefits of an ethanolic Alhagi maurorum extract against the probable neurotoxicity of topiramate. Methods: The following were given orally to rats for a month in four groups: distilled water, topiramate (400 mg/kg daily), Alhagi maurorum ethanolic extract (300 mg/kg daily), and topiramate plus A. maurorum extract (AME). In the sciatic nerve, RT-qPCR was utilized to measure the levels of transcriptional mRNA of antioxidant genes, with biochemical levels of oxidative stress indicators, s100, neurospecific enolase, serum phosphorylated neurofilament-H, and acetylcholinesterase (AchE) were estimated. Histopathological examination and the expression of nitrotyrosine and myelin basic protein were assessed. Results: Topiramate increased levels of neurospecific enolase, s100, neurotransmitter AchE, Serum phosphorylated neurofilament-H, and oxidative stress markers while decreasing antioxidant genes' transcriptional mRNA levels. Within the sciatic nerve, topiramate also resulted in a variety of neuropathological alterations, notable nitrotyrosine immune reactivity, and moderate myelin basic protein immune reactivity. Supplementing with A. maurorum extract did not cause any neurotoxicity. Antioxidant gene transcriptional mRNA levels rose in response to A. maurorum extract supplementation, and all aberrant measures were nearly normal. Conclusion: the sciatic nerve of rats exposed to topiramate may be protected by the A. maurorum extract by preventing oxidative stress and apoptosis.