<p>Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) pose serious threats to human health, and their pathogenesis is closely related to mitochondrial damage. Mitochondrial dysfunction includes abnormal energy metabolism, oxidative stress imbalance, disturbed calcium homeostasis and altered mitochondrial dynamics, which in turn trigger neuronal apoptosis and neuroinflammation. Mitochondrial dysfunction is a hallmark of many NDs. In addition to their multi-lineage differentiation potential, ability to promote neuronal repair, and capacity to modulate the neuroimmune microenvironment, Mesenchymal stem cells (MSCs) also hold potential for restoring mitochondrial dysfunction. MSCs have important therapeutic potential and mechanistic research value in the context of neurodegenerative disorders through the modulation of mitochondrial homeostasis and its transcellular transfer process. In this paper, we systematically summarize the mechanisms, technological advances, and translational challenges associated with mitochondrial damage in NDs and the role of MSCs in NDs through the modulation of mitochondrial damage and discuss their potential and limitations as a general therapeutic strategy.</p>