<p>Chronic high-dose ketamine, widely recognized for its rapid antidepressant effects, poses significant risks to brain health, particularly in the hippocampus, a region critical for learning, memory, and emotional regulation. This narrative review aims to elucidate the molecular mechanisms underlying ketamine-induced apoptosis in hippocampal neurons, providing a comprehensive synthesis of current research findings. We examine how chronic exposure to high doses of ketamine disrupts glutamatergic signaling through NMDA receptor antagonism, leading to an imbalance in excitatory neurotransmission that triggers apoptotic pathways. Additionally, we explore the roles of neuroinflammation and oxidative stress in exacerbating neuronal vulnerability, highlighting the interplay between these mechanisms. The review discusses how chronic ketamine use activates glial cells, resulting in the release of pro-inflammatory cytokines and increased oxidative damage, further promoting neuronal cell death. Furthermore, we consider the implications of altered neurotrophic factor signaling and mitochondrial dysfunction in the context of ketamine’s neurotoxic effects. By integrating these molecular pathways, we provide insights into the critical factors contributing to ketamine-induced apoptosis. Finally, we highlight the need for further research to clarify the dose-response relationship, individual variability in treatment outcomes, and potential neuroprotective strategies. Ultimately, this review emphasizes the importance of balancing the therapeutic benefits of ketamine with its associated risks, advocating for a nuanced understanding of its long-term effects on brain health to inform clinical practices and optimize patient care.</p> Graphical Abstract <p></p>