Epilepsy is a chronic neurological disorder often complicated by drug resistance and comorbidities, with limited benefits from conventional therapies. This review explores the role of neuro-immune interactions in epilepsy, detailing a core mechanism where seizures disrupt the blood-brain barrier, enabling immune cell infiltration and activating glial cells to release pro-inflammatory factors, thus perpetuating a vicious cycle. Key signaling pathways are also discussed. The article surveys diagnostic advances, including neuro-immune biomarkers and technologies like multimodal imaging and single-cell sequencing. For treatment, immunomodulatory strategies—such as targeting inflammation, modulating glial cells or gut microbiota, and cell therapies—as well as the development of novel anti-seizure medications​ are summarized. Current challenges involve controversies over immune cell functions and inflammatory causality, as well as limitations in animal models and clinical translation. Future directions like multi-omics integration, artificial intelligence, and novel delivery systems are highlighted, offering a new paradigm for precise, etiology-targeted therapy in drug-resistant epilepsy.