Background: Nerve growth factor (NGF) shows neuroprotection while it is hard to cross the blood-brain barrier due to its large molecular weight. Our study used intranasal delivery of NGF to treat the experimental epilepsy. Methods: The seizure was induced by injection of pentylenetetrazol (40 mg/kg) into the rat. Based on the behavior performance, the successful models were randomized into control and NGF groups, given medium or NGF intranasally, respectively. The onset and duration of seizure were recorded. The neuron loss was assessed by immunohistochemistry and TUNEL staining. The expressions of Caspase-3, p75R and TrkA were measured by western blotting. Results: Intranasal NGF significantly reduced the seizure onset and shortened the seizure duration. Intranasal NGF alleviated the neuron loss in the epileptic brain. The number of TUNEL-positive cells in the NGF group was less than that in the control group (P < 0.05). Overexpression of Caspase-3 and activation of p75R induced by seizure were inhibited by intranasal NGF. Conclusion: Intranasal NGF protected neurons in the epileptic brain by inactivation of p75R/Caspase pathway. Intranasal NGF may be a novel therapeutic strategy for epilepsy.