Mitochondrial function is vital for normal cellular processes. Mitochondrial damage and oxidative stress have been greatly implicated in the progression of aging, along with the pathogenesis of age-related neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Although antioxidant therapy has been proposed for the prevention and treatment of age-related NDs, unraveling the molecular mechanisms of mitochondrial dysfunction can lead to significant progress in the development of effective treatments against such diseases. Aging is associated with the generation and accumulation of reactive oxygen species (ROS) that are the major contributors to oxidative stress. Oxidative stress is caused because of the imbalance between the production of ROS and their oxidation, which can affect the mitochondrial respiratory chain function, thereby altering the membrane permeability and calcium homeostasis, along with increasing the heteroplasmic mtDNA and weakening the mitochondrial defense systems. Mitochondrial dysfunction mainly affects mitochondrial biogenesis and dynamics that are prominent in several age-related NDs. Mitochondrial dysfunction has a crucial role in the pathophysiology of age-related NDs. Several mitochondria targeted strategies, such as enhancing the antioxidant bioavailability via novel delivery systems, identifying unique mitochondrial proteins as specific drug targets, investigating the signaling pathways of mitochondrial biogenesis and dynamics, and identifying effective natural products are potentially effective to counteract mitochondrial dysfunction-related NDs.