<p>Parkinson’s disease (PD), the second most common neurodegenerative disorder worldwide, currently lacks effective treatment options due to its complex pathogenesis. Growing evidence in recent years demonstrates that intracellular Calcium (Ca²⁺) homeostasis disruption plays a critical role in PD development and progression. Ca²⁺ imbalance not only causes Ca²⁺-dependent synaptic dysfunction and impaired neuronal plasticity but also leads to progressive neuronal loss, collectively forming the core pathological characteristics of PD neurodegeneration. Notably, mitochondrial Ca²⁺ imbalance has been identified as a key pathogenic factor in PD. As vital intracellular Ca²⁺ regulators, dysfunctional mitochondria can induce abnormal opening of the mitochondrial permeability transition pore (mPTP), triggering apoptotic cascades. Furthermore, mitochondrial Ca²⁺ overload disrupts oxidative phosphorylation, resulting in excessive reactive oxygen species production that exacerbates neuronal damage. Recent studies reveal the essential role of mitochondria-endoplasmic reticulum interactions in maintaining Ca²⁺ homeostasis, with these organelles forming structurally and functionally integrated connections through mitochondrial ER-associated membrane (MAM) to cooperatively regulate Ca²⁺ ion dynamics. This review describes the molecular mechanisms of mitochondrial Ca²⁺ imbalance in PD pathogenesis and summarizes the potential of mitochondrial channels and MAM-associated proteins as PD therapeutic targets. By thoroughly analyzing these targets mechanisms, we aim to provide a theoretical foundation for developing novel PD treatment strategies based on Ca²⁺ homeostasis regulation. These findings not only expand our understanding of PD pathogenesis but also point toward developing targeted neuroprotective therapies.</p>