MicroRNAs (miRNA) are known as a key role in the etiology and treatment of epilepsy through controlling the expression of gene. However, miR-125a-5p in the epilepsy is little known. The epilepsy rat models were induced by pentylenetetrazol (PTZ) and miR-125a-5p profiles in the hippocampus were investigated in our experiment. Also, the relation between miR-125a-5p and calmodulin-dependent protein kinase IV (CAMK4) was identified and related mechanism was illustrated.The miR-125a-5p mRNA expression levels were evaluated by quantitative real time polymerase chain reaction (qRT-PCR), western blot (WB) was used to analyze the CAMK4 protein expression levels. Seizure score, latency and duration were determined based on a Racine scale. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the inflammatory factor expression. The relationship between miR-125a-5p and CAMK4 was detected through dual luciferase assay.Downregulation of miR-125a-5p was found in hippocampus of PTZ-induced epilepsy rats. miR-125a-5p overexpression attenuated seizure and decreased inflammatory factor level in hippocampus of PTZ-induced rats. miR-125a-5p alleviated epileptic seizure and inflammation of PTZ-induced by suppressing its target gene, CAMK4.miR-125a-5p may represent a novel therapeutic treatment for PTZ-induced epilepsy by preventing the activation of CAMK4.