Sirtuin 5 (SIRT5) is a nicotinamide adenine dinucleotide (NAD+)-dependent desuccinylase. It is mainly located in the mitochondrial matrix and is closely related to mitochondrial metabolism and redox process. In recent years, great progress has been made on the role of SIRT5 in cardiovascular and cerebrovascular diseases, neurodegenerative diseases and tumorigenesis. This review summarizes the latest progress in desuccinylation of SIRT5 and its mechanism in nervous system diseases.