The basal concentrations of extracellular Zn²⁺ and intracellular Zn²⁺, which are approximately 10 nM and 100 pM, respectively, in the brain, are markedly lower than those of extracellular Ca²⁺ (1.3 mM) and intracellular Ca²⁺ (100 nM), respectively, resulting in much less attention paid to Zn²⁺ than to Ca²⁺. However, intracellular Zn²⁺ dysregulation, which is closely linked with glutamate- and amyloid β-mediated extracellular Zn²⁺ influx, is more critical for cognitive decline and neurodegeneration than intracellular Ca²⁺ dysregulation. It is estimated that the age-dependent increase in the basal concentration of extracellular Zn²⁺ in the hippocampus plays a key role in cognitive decline and neurodegeneration. The characteristics of extracellular Zn²⁺ influx in the hippocampus may be modified age-dependently, probably followed by modification of intracellular Zn²⁺ buffering that is closely linked with age-related cognitive decline and neurodegeneration. Reduction of intracellular Zn²⁺-buffering capacity may be linked with the pathophysiology of progressive neurodegeneration such as Alzheimer’s disease. This paper deals with age-dependent modification of intracellular Zn²⁺ buffering in the hippocampus and its impact. On the basis of the estimated impact, we propose a potential defense strategy against Zn²⁺-mediated neurodegeneration, i.e., metallothionein induction in the hippocampus.