<p>Normal functioning of the brain consists of a complex set of physiological interactions occurring within specific anatomical sites of the brain. One of the most important areas within the brain responsible for a cohort of these homeostatic actions is the hippocampus. The hippocampus serves as a critical nexus for memory, emotion, and cognition. However, the widespread and often long-term use of psychotropic medications, particularly benzodiazepines, has raised concern regarding their potential structural and functional effects on this vulnerable region. Chronic benzodiazepine use remains common in psychiatric practice despite increasing concern regarding its long-term effects on hippocampal structure and cognitive health. As a neuroanatomical target of psychotropic medications, the hippocampus may be particularly susceptible to sustained pharmacologic modulation. Pharmaceutical drugs designed to modulate these hippocampal functions are not without potentially deleterious side effects. One such medication group, benzodiazepines, has been highlighted for its pleiotropic effects on hippocampal function. Evidence highlights that while chronic benzodiazepine use may diminish hippocampal volume, impair neuroplasticity, and heighten dementia risk, other medications such as lithium, gabapentin, and potential naturalistic treatments appear to counteract these effects by enhancing neurogenesis, synaptic resilience, and structural preservation. These GABAergic modulators, in combination with naturalistic modulators, further emphasize the potential for therapies that protect or even restore hippocampal integrity, offering promising alternatives to conventional treatments regarding chronic benzodiazepine use. Taken together, these findings reinforce the need for judicious prescribing practices and more research into neuroprotective strategies. The long-term structural health of the hippocampus carries direct implications for cognitive vitality and positive psychiatric outcomes. The use of lithium, in particular, may help mitigate benzodiazepine-associated adverse structural changes and potentially reduce the burden of neurodegenerative processes linked to hippocampal dysfunction. This review synthesizes current evidence regarding benzodiazepine-associated hippocampal changes and explores potential neuroprotective interventions that may mitigate structural vulnerability or support cognitive resilience.</p>