Hepatocytes, the predominant cellular constituents of the liver, exhibit the highest mitochondrial density within the human body. Remarkably, experimental insights from the latter part of the previous century involving extracellular injection of mitochondrial DNA (mtDNA) elucidated its potential to incite autoimmune disorders. Consequently, in instances of liver injury, the substantial release of mtDNA has the potential to trigger the activation of the innate immune response, thereby inducing sustained pathogenic consequences within the organism. This article provides a comprehensive retrospective analysis of recent literature pertaining to the impact of mtDNA release on various hepatic cell populations, elucidating its role and potential mechanisms in liver injury. The findings underscore the central role of mtDNA in modulating the immune system, primarily through the orchestration of a cytokine storm, further exacerbating the occurrence of liver injury.