Epilepsy, a neurological illness, is characterized by recurrent uncontrolled seizures. There are many treatments of options that can be used as the therapy of epilepsy. However, anti-seizure medications as the primary treatment choice for epilepsy show many possible adverse effects and even pharmacoresistance to the therapy. High Mobility Group Box 1 (HMGB1) as an initiator and amplifier of the neuroinflammation is responsible for the onset and progression of epilepsy by overexpressing P-glycoprotein on the blood brain barrier. HMGB1 proteins then activate TLR4 in neurons and astrocytes, in which proinflammatory cytokines are produced. Anti-HMGB1 mAb works by blocking the HMGB1, reducing inflammatory activity in the brain that may affect epileptogenesis. Through the process, anti-HMGB1 mAb reduces the TLR4 activity and other receptors that may involve in promote signal of epilepsy such as RAGE. Several studies have shown that anti-HMGB1 has the potential to inhibit the increase in serum HMGB1 in plasma and brain tissue. Further research is needed to identify the mechanism of the inhibiting of overexpression of P-glycoprotein through anti-HMGB1 mAb.