BACKGROUND: Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally, with temporal lobe epilepsy (TLE) being the most common form. Despite advances in antiepileptic drug development, over 30% of patients suffer from drug-resistant epilepsy, which can lead to severe cognitive impairments and adverse psychosocial outcomes. AIM: To explore the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy, providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy. METHODS: Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each, and the TLE model group was established by injecting kainic acid. BMSCs were isolated from the mice, and exosomes were purified using ultracentrifugation. Exosomal miR-203 was identified and characterized using high-throughput sequencing and quantitative reverse-transcription polymerase chain reaction. The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using RESULTS: Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice. CONCLUSION: Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy. The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway, thus providing a potential avenue for the development of cell-free therapeutics.