Mitochondrial dysfunction and endoplasmic reticulum stress are emerging as central, interconnected contributors to the pathogenesis of neurodegenerative diseases. This chapter delves into the synergistic disruption of mitochondrial dynamics and endoplasmic reticulum proteostasis, emphasizing their role in promoting oxidative stress, calcium dysregulation, neuroinflammation, and autophagic failure. Special focus is placed on mitochondrial membranes, which facilitate critical crosstalk between organelles and serve as hubs of pathological signaling when disrupted. Key molecular mechanisms such as dynamin-related protein 1-mediated mitochondrial fission, Protein kinase R-like endoplasmic reticulum kinase-C/EBP homologous protein-driven endoplasmic reticulum stress-induced apoptosis, and the breakdown of mitochondrial membrane integrity are highlighted to elucidate the progression of neuronal damage. Additionally, this chapter discusses recent advances in targeted therapies, including mitochondrial reactive oxygen species scavengers and endoplasmic reticulum stress modulators. Clinical relevance is underscored through disease-specific examples such as amyloid β-induced endoplasmic reticulum stress in Alzheimer’s and superoxide dismutase 1 mutations in amyotrophic lateral sclerosis, offering insight into promising therapeutic interventions aimed at restoring organelle homeostasis in neurodegenerative diseases.