Neurodegenerative diseases are a group of disorders characterized by chronic progressive degeneration of neurons in the brain and/or spinal cord. Their etiology remains unclear, the pathogenesis is complex, and no effective treatments exist. Importantly, the roles of mitochondria-localized silent information regulator (SIRT) family members, including SIRT3, SIRT4, and SIRT5, in neurodegenerative diseases are attracting increasing attention. Accumulating evidence demonstrates their involvement in critical processes of neuronal degeneration by regulating, for example, mitochondrial function and inflammatory responses. This review summarizes the research advances on mitochondrial SIRTs in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, and aims to provide new insights for elucidating disease pathogenesis and developing prevention/therapeutic strategies.