<p>Epilepsy is a prevalent neurological disorder whose pathogenesis is closely associated with blood–brain barrier (BBB) disruption. Emerging evidence suggests that astrocytic pyroptosis may play a pivotal role in BBB impairment. Based on this, we propose two central hypotheses: (1) seizure activity triggers astrocytic pyroptosis and exacerbates BBB damage; (2) pharmacological inhibition of pyroptosis can restore BBB integrity and alleviate epileptic symptoms. This study established a kainic acid-induced mouse model of epilepsy and an in vitro BBB model. Cell pyroptosis was induced using LPS and ATP. The expression of BBB and pyroptosis-related proteins was assessed through Western blotting, immunofluorescence, and RT-PCR. Additionally, a pyroptosis inhibitor, disulfiram (DSF), was used to inhibit pyroptosis, and the therapeutic effects on epilepsy were evaluated through behavioral experiments, electroencephalography, and electron microscopy. BBB damage and pyroptosis were observed in the hippocampal tissue of mice following seizures, with immunofluorescence results indicating the occurrence of pyroptosis in astrocytes. In vitro experiments demonstrated that astrocyte pyroptosis leads to the downregulation of tight junction proteins in endothelial cells. Inhibition of pyroptosis by DSF improved the integrity of the BBB and resulted in reduced severity of seizure activity and improved cognitive function in mice. This study reveals the role of astrocyte pyroptosis in seizure activity and the consequent BBB damage. DSF mitigates seizure severity and cognitive impairment by inhibiting astrocyte pyroptosis and improving BBB integrity, offering new insights and targets for epilepsy treatment.</p>