<p>Mitochondrial ion channels and transporters are pivotal for cellular bioenergetics, signalling, and homeostasis, with the sodium-calcium-lithium exchanger (NCLX) emerging as a critical regulator of mitochondrial calcium dynamics. By extruding calcium in exchange for sodium or lithium ions, NCLX prevents calcium overload, a key contributor to mitochondrial dysfunction and cell death. While previous reviews have explored NCLX in the context of specific diseases or immune cell function, this article provides a comprehensive analysis of its role across multiple disease states, including cardiovascular, neurological, metabolic, and pregnancy-related conditions. Moreover, it highlights the potential of ethnobotanical compounds such as resveratrol and curcumin as therapeutic candidates targeting NCLX. By integrating insights from structural biology, disease mechanisms, and emerging therapeutic strategies, this review aims to advance our understanding of NCLX’s role in pathophysiology and explore novel avenues for its targeted modulation in diseases characterized by disrupted mitochondrial calcium homeostasis.</p>