Epilepsy is a common chronic neurological disease in children, whose recurrent seizures tend to cause irreversible brain damage and bring heavy burdens to their families. Currently, approximately one-third of patients with epilepsy are refractory to medical treatment and constantly suffer from recurrent seizures. Therefore, new therapeutic strategies are in urgent need. Recent studies have found that sequestosome 1/p62, a key molecule of autophagy, may be involved in regulating multiple signaling pathways through its multifunctional domains, including mammalian target of rapamycin complex 1 (mTORC1) signaling and inflammatory signaling pathways. Therefore, it is of great significance to explore the role of p62 protein in epilepsy and the underlying mechanisms. This article discusses the structure and function of p62 protein and reviews the associated mechanisms and potential therapeutical effects of p62 protein in epilepsy.