Mitochondrial DNA (mtDNA) is the circulating genome in mitochondria, and it is easy to accumulate oxidative damage, causing mitochondrial dysfunction, and then cell dysfunction, and even tissue and body pathological changes, leading to diseases. As a pro-inflammatory, inflammatory, and even predictive factor, mtDNA is directly involved in the inflammatory response and the pathogenesis of many diseases. This article aims to review the current pathogenesis of mtDNA damage and its pathogenic role in various human diseases.