<p>Epilepsy is often marked by paroxysmal seizures that disrupt the brain’s sensory, motor, and psychosocial functions. The underlying pathology is generally believed to involve an imbalance between excitatory and inhibitory neurotransmission. However, a less explored but significant contributor to epilepsy is the collapse of the brain’s metabolic and bioenergetic systems. The breakdown of the brain’s bioenergetic system leads to the activation of various detrimental downstream signaling cascades that ultimately result in oxidative stress, neuroinflammation, and reduced autophagic flux, all of which impair neuronal-glial communication and precipitate epileptic attacks. This highlights the pressing need for a therapeutic agent to address these complex challenges. Researchers have identified adenosine monophosphate kinase (AMPK) as a potential solution. AMPK acts as the body’s primary stress sensor, activated in response to the deficiency of growth factors and nutrient starvation to restore energy homeostasis. AMPK activation also maintains the intricate communication between neurons and glial cells, preserving synaptic plasticity integrity, mitigating mitochondrial damage, and dampening inflammatory signaling cascades. Despite demonstrating significant efficacy in managing a range of peripheral and neurological disorders, the role of AMPK in neurotransmission and epilepsy remains unexplored. This review explores the multifaceted molecular roles of AMPK beyond its traditional metabolic regulatory functions, suggesting that targeting AMPK could provide a novel avenue for drug development in epilepsy treatment.</p> Graphical Abstract <p></p>