Zinc the essential trace element, plays a significant role in the brain development and in the proper brain functions at every stage of life. Misbalance of zinc (Zn²⁺) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as Alzheimer's disease, Depression, and Epilepsy. In brain, Zn²⁺ has been identified as a ligand, capable of activating and inhibiting the receptors including the NMDA-type glutamate receptors (NMDARs), GABA_A receptors, nicotinic acetylcholine receptors (nAChRs), glycine receptors (glyR) and serotonin receptors (5-HT3). Recently GPR39 has been identified as a zinc-specific receptor, widely expressed in brain tissues including the frontal cortex, amygdala, and hippocampus. GPR39, when binding with Zn²⁺ has shown promising therapeutic potentials. This review presents current knowledge regarding the role of GPR39 zinc sensing receptor in brain, with a focus on Alzheimer’s disease and Epilepsy. Although the results are encouraging, further research is needed to clarify zinc and GPR39 role in the treatment of Alzheimer's disease and Epilepsy.