Approximately 30% of epilepsy cases are refractory to current pharmacological treatments. Thus, novel therapeutic approaches that prevent or reverse the molecular and cellular mechanisms of epilepsy are required. 5-HT6 receptor (HTR6) blockade can modulate multiple neurotransmitter systems, and HTR6 may be a potential therapeutic treatment for neurological diseases, including epilepsy. Here, we investigated the role of HTR6 in epilepsy. We detected HTR6 expression both in human epileptic tissues and the pilocarpine rat model by western blotting. We observed behavioral changes after administration of pilocarpine in rats pretreated with a selective HTR6 antagonist, SB-399885, and recorded the electrophysiological index in the pilocarpine rat model pre- or posttreated with SB-399885 by electroencephalogram (EEG) and whole-cell clamp. We measured the activity of mammalian target of rapamycin (mTOR) in the pilocarpine rat model pretreated with the mTOR-specific inhibitor, rapamycin, and SB-399885 using western blotting. We found that HTR6 expression was upregulated in both human tissues and the pilocarpine rat model, and that SB-399885 could suppress epileptic seizures and mTOR activity in epileptic seizures. These results suggest that HTR6 plays an important role in modulating seizure activity and that the blockade of the HTR6/mTOR pathway could be a potential therapeutic target for epilepsy treatment.