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Background Accumulating evidence demonstrates that certain microRNAs play critical roles in epileptogenesis. Our previous studies found microRNA (miR)‐129–2‐3p was induced in patients with refractory temporal lobe epilepsy (TLE). In this study, we aimed to explore the role of miR‐129–2‐3p in TLE pathogenesis. Method By bioinformatics, we predicted miR‐129–2‐3p may target the gene GABRA1 encoding the GABA type A receptor subunit alpha 1. Luciferase assay was used to investigate the regulation of miR‐129–2‐3p on GABRA1 3’UTR. The dynamic expression of miR‐129–2‐3p and GABRA1 mRNA and protein levels were measured in primary hippocampal neurons and a rat kainic acid (KA)‐induced seizure model by quantitative reverse transcription‐polymerase chain reaction (qPCR), Western blotting, and immunostaining. MiR‐129–2‐3p agomir and antagomir were utilized to explore their role in determining GABRA1 expression. The effects of targeting miR‐129–2‐3p and GABRA1 on epilepsy were assessed by electroencephalography (EEG) and immunostaining. Results Luciferase assay, qPCR, and Western blot results suggested GABRA1 as a direct target of miR‐129–2‐3p. MiR‐129–2‐3p level was significantly upregulated, whereas GABRA1 expression downregulated in KA‐treated rat primary hippocampal neurons and KA‐induced seizure model. In vivo knockdown of miR‐129–2‐3p by antagomir alleviated the seizure‐like EEG findings in accordance with the upregulation of GABRA1. Furthermore, the seizure‐suppressing effect of the antagomir was partly GABRA1 dependent. Conclusions The results suggested GABRA1 as a target of miR‐129–2‐3p in rat primary hippocampal neurons and a rat kainic acid (KA) seizure model. Silencing of miR‐129–2‐3p exerted a seizure‐suppressing effect in rats. MiR‐129–2‐3p/GABRA1 pathway may represent a potential target for the prevention and treatment of refractory epilepsy., Accumulating evidence demonstrates that certain microRNAs play critical roles in epileptogenesis. In this study, we found GABA type A receptor subunit alpha 1 (GABRA1) as a direct target of miR‐129–2‐3p, resulting in the downregulation of GABRA1 expression. Silencing of miR‐129–2‐3p exerted a seizure‐suppressing effect in KA‐induced seizure model, and miR‐129–2‐3p/GABRA1 pathway may represent a potential target of the prevention and treatment of refractory epilepsy.