Epilepsy is a relatively common chronic neurological condition that is often characterized by unprovoked recurrent seizures that can be very disruptive for the lives of patients and their families. Na⁺ / K⁺ -ATPase (NKA) is a transmembrane protein distributed widely in most cells of mammalian animals. NKA is critical for the maintenance of the ionic gradient between intracellular and extracellular space, the uptake and release of neurotransmitters, and energy metabolism. Complicated patterns of change in NKA activity have been observed in the brains of epileptic patients and animals. Excessive changes in NKA activity may upregulate susceptibility to epilepsy in non-human animals, although NKA activity decreases significantly after recurrent seizures. In this article, we reviewed the classification, distribution, and function of NKA, as well as interactions and possible mechanisms between NKA activity and seizures.