Summary Sirtuin 2 ( SIRT 2) is a member of a family of NAD + ‐dependent histone deacetylases ( HDAC ) that play diverse roles in cellular metabolism and especially for aging process. SIRT 2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system ( CNS ), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT 2 in the nervous system specifically during aging. Here, we show that middle‐aged, 13‐month‐old mice lacking SIRT 2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT 2 mice. In addition, these Sirt2 −/− mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between SIRT 2 and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for SIRT 2 in orchestrating its metabolic regulation. This underscores the value of SIRT 2 as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis.