Objective To preliminarily explore the effects and brain protective mechanism of intermittent hypoxia preconditioning (IHP) on rats with seizures induced by lithium-pilocarpine (Li-pilo). Methods A total of 96 8-week old male Sprague Dawley rats (clean grade) were randomly divided into control group,seizure group and four IHP-seizure groups. The animal model of epilepsy was established by intraperitoneal injection of Li-pilo in the seizure group and four IHP-seizure groups (Li-pilo was injected at 1, 3, 7, or 14 days after a 5-day regimen of IHP). Subsequent seizure behavior, the latency period and percentage of generalized seizures were quantitatively evaluated for 240 min and the cognitive function was tested by Morris water maze task, and followed by the detection of hippocampus neuron apoptosis and related protein (BCL-2, Bax, and cleaved-caspase-3) by TUNEL labeling and Western blot, respectively. Results The induced seizure peaked on an average between 50-150 min after Li-pilo administration, scored using a modified Racine scale. The average scores of modified Racine scale in the IHP-3d seizure group was significantly lower than that in the other groups. The latency period and percentage of generalized seizures in the IHP-3d seizure group rats were significantly different from the parameters in the seizure group rats (P<0.05). IHP-3d seizure rats showed lower escape latency, neuronal apoptosis counts and higher percentage of time in the probe quadrant compare with the seizure group and the other three IHP-seizure groups (P<0.05). Compared with the control group, the parameters of water maze and apoptosis detection in the IHP-3d seizure group showed no significant changes (P>0.05). Conclusions The results indicate that IHP treatment may help to decrease the susceptibility to epilepsy by reducing abnormal apoptosis, and has a brain protective effect on the seizure rats.