The study identifies the fasciola cinereum (FC) neurons of the posterior hippocampal tail as a critical seizure node in both mice and humans with epilepsy. In mice, FC neurons were highly active during spontaneous seizures, and optogenetic inhibition of these neurons significantly reduced seizure duration. In humans, FC involvement was observed in six patients with epilepsy, suggesting its role in seizure propagation. Targeted lesioning of the FC in a patient reduced seizure burden after ablation of anterior mesial temporal structures. These findings indicate that the FC may be a promising interventional target for epilepsy treatment.The study identifies the fasciola cinereum (FC) neurons of the posterior hippocampal tail as a critical seizure node in both mice and humans with epilepsy. In mice, FC neurons were highly active during spontaneous seizures, and optogenetic inhibition of these neurons significantly reduced seizure duration. In humans, FC involvement was observed in six patients with epilepsy, suggesting its role in seizure propagation. Targeted lesioning of the FC in a patient reduced seizure burden after ablation of anterior mesial temporal structures. These findings indicate that the FC may be a promising interventional target for epilepsy treatment.