Amentoflavone is a natural biflavone compound with many biological properties, including anti-inflammatory, antioxidative, and neuroprotective effects. We presumed that amentoflavone exerts a neuroprotective effect in epilepsy models. Prior to model establishment, mice were intragastrically administered 25 mg/kg amentoflavone for 3 consecutive days. Amentoflavone effectively prevented pilocarpine-induced epilepsy in a mouse kindling model, suppressed nuclear factor-κB activation and expression, inhibited excessive discharge of hippocampal neurons resulting in a reduction in epileptic seizures, shortened attack time, and diminished loss and apoptosis of hippocampal neurons. Results suggested that amentoflavone protected hippocampal neurons in epilepsy mice via anti-inflammation, antioxidation, and antiapoptosis, and then effectively prevented the occurrence of seizures. A pre-administration of 25 mg / kg amentoflavone for 3 Sustained discharge of hippocampal neurons resulting in a reduction in epileptic seizures, shortened attack time, and diminished loss and apoptosis of hippocampal Neurons. Results suggested that amentoflavone protected hippocampal neurons in epilepsy mice via anti-inflammation, antioxidation, and antiapoptosis, and then essentially prevented the occurrence of seizures.