Mitochondria play a pivotal role in the fatty acid oxidation and have been found to be affected early during the macrovesicular fat accumulation in the hepatocytes. The fatty infiltration is the primary cause of oxidative stress and inflammation in the non‐alcoholic fatty liver disease (NAFLD), which can lead to the peroxidation of phospholipids, such as cardiolipin. Oxidative stress‐induced damage to mitochondrial DNA can result in the impairment of oxidative phosphorylation and further increases the generation of reactive oxygen species. The mitochondrial damage may eventually lead to apoptotic death of hepatocytes. The apoptosis along with the generated cytokines from the stellate and Kupffer cells further augment the fibrotic changes to advance the disease. Hence, alleviation of the mitochondrial impairment, particularly in the early stages of NAFLD, may prevent the progression of the disease. Among the various experimentally studied mitochondrial‐targeted agents, triphenylphosphonium cation ligated ubiquinone Q10 and vitamin E, Szeto‐Scheller peptides, and superoxide dismutase mimetic‐salen manganese complexes (EUK‐8 and EUK‐134) have been found to be most promising. In addition to these mitochondrial‐targeted agents, a novel area of therapy called mitotherapy have also emerged. However, clinical studies conducted so far are still fragmentary to validate their efficacy. This review article discusses the mitochondria‐targeted molecules and their potential role in the treatment of NAFLD.