Epilepsy is a chronic disease caused by an increased excitability of nerve cells in the brain, characterized by two or more unprovoked seizures, which can be attributed to genetic or acquired causes. There are currently more than 50 million people worldwide who have epilepsy, and this number is continuously increasing. Although significant advancements have been made regarding the diagnosis and treatment of epilepsy in recent years, our knowledge about the cellular and molecular mechanisms underlying the development of epilepsy or epileptogenesis is still insufficient. The absence of a specific biomarker for diagnosis makes epilepsy relatively challenging to diagnose. Therefore, the discovery and implementation of specific markers are important for the diagnosis and early treatment of epilepsy. The S100 protein family is a group of low molecularweight proteins that are localized in the cytoplasm and/or nucleus of various cells. These proteins play a regulatory role in various intracellular processes, including the cell cycle, by localizing within the cytoplasm and nucleus of the cell. S100B is a member of the S100 family. Its functions are highly concentration-dependent, at physiological concentrations, it exhibits a neuroprotective function, supporting neural survival and stimulating dendrites and axons. However, at high concentrations, it induces neuronal apoptosis, activates pro-inflammatory cytokines, and stress-induced inflammatory enzymes. When brain cells are damaged or destroyed, S100B proteins are released from the cells and can be detected in the blood. S100B can be considered as a prognostic biomarker that can be used for diagnosing epilepsy in clinical practice. This review summarizes the role of the S100B protein in epilepsy.