Alcoholic liver disease and acetaminophen overdose are common causes of severe liver disease and liver failure in the United States for which there is no cure. Therefore, development of new therapeutic strategies for treatment of liver injury caused by acetaminophen and alcohol is needed. We demonstrated that autophagy protects against alcohol and acetaminophen-induced liver injuries by removing damaged mitochondria via mitophagy, which is a selective form of autophagy specific for degradation of damaged mitochondria. Parkin is well-known to be required for mitophagy induction in in vitro models, and we previously showed that the Parkin-mediated mitophagy pathway likely plays a protective role against alcohol and acetaminophen-induced liver injuries. Therefore, pharmacological upregulation of the Parkin-mediated mitophagy pathway in the liver may provide a novel and effective therapeutic option for treatment of acetaminophen and alcohol-induced liver injuries. In this review, we discuss regulation of Parkin-mediated mitophagy and possible therapeutic targets of intervention in this pathway.