Lon protease (LON) is a highly conserved ATP-dependent serine protease, which is responsible for the decomposition and elimination of abnormal proteins. As an important executor of intracellular environment stability, LON can degrade misfolded and damaged proteins together with proteasome to ensure the high quality of proteins in vivo, especially in the maintenance of mitochondrial function. At the same time, the physiological function of LON also has an important effect on cell survival under various stresses. Recent studies have shown that the abnormal expression or activity of LON is involved in the occurrence and development of many diseases such as neurodegenerative diseases, diabetes mellitus, myocardial ischemia, cerebral ischemia and tumors. This review focuses on the structure and the function of LON, the relationship between abnormal expression and diseases, and the research progress of LON activity intervention, in order to provide ideas for clinical diagnosis and treatment of related diseases.