Zinc (Zn²⁺) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn²⁺ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn²⁺ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn²⁺ levels, we employed the Zn²⁺ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn²⁺ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn²⁺ levels. Our findings confirm the importance of targeting Zn²⁺ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn²⁺ availability upon the early stages of development.