Mitochondria dysfunction is associated with apoptotic resistance and metabolism of tumor cells. Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with multiple genetic aberrations. Certain gene mutations in mitochondria may lead to mitochondrial dysfunction. The p53 family plays a key role in the mitochondrial apoptosis pathway and acts as part of the molecular mechanisms underlying mitochondrial dysfunction in HCC. The novel genes found in the mitochondrial apoptosis signaling pathways, such as mfn2, play a role in the p53 network. In mitochondrial metabolism, expression of certain genes may be associated with apoptosis when they are involved in hepatocarcinogenesis. MicroRNAs have also been found to play a role in this process. Some genes may even exhibit multiple functions in the mitochondrial dysfunction of HCC. In HCC therapy, genes have also been found to influence the chemotherapeutic treatment by killing cells via the apoptosis pathway or autophagy. Investigation of mitochondrial dysfunction-related genes could potentially provide evidence for novel therapies that target HCC.