Status epilepticus (SE) is a life-threatening disorder associated with neuronal pyroptosis. This study aims to explore the mechanism of HDAC1 in hippocampal neuronal pyroptosis induced by kainic acid in mice, providing a theoretical basis for SE treatment. A mouse model of SE was established by kainic acid. After sh-HDAC1 injection, the severity of SE and hippocampal neuronal damage were assessed. Cell model was established using kainic acid-induced HT22, followed by detection of HDAC1, miR-15a-5p, Caspase-1, cleaved Caspase-1, H3K9ac, and GSDMD-N using qRT-PCR and Western blot assays. Levels of IL-1β, IL-18, and LDH were measured. The enrichment of HDAC1 on the miR-15a-5p promoter was detected. The binding of miR-15a-5p to Caspase-1 was validated. We found that HDAC1 was highly expressed in kainic acid-induced SE. HDAC1 knockdown alleviated the symptoms of SE, inhibited cleaved Caspase-1, GSDMD-N, IL-1β, and IL-18, and suppressed hippocampal neuronal pyroptosis. HDAC1 bound to the miR-15a-5p promoter and reduced H3K9ac, thereby inhibiting miR-15a-5p expression. miR-15a-5p bound to Caspase-1 and inhibited Caspase-1 expression. Inhibiting miR-15a-5p or overexpressing Caspase-1 partially reversed the inhibitory effect of si-HDAC1 on kainic acid-induced cell pyroptosis. In conclusion, HDAC1 aggravates hippocampal neuronal pyroptosis in SE via the miR-15a-5p/Caspase-1 axis through deacetylation of H3K9.