Autophagy is a highly conserved cell program in eukaryotic cells, which plays an important role for cells to deal with adverse external stimuli such as ischemia-reperfusion. Tanshinone IIA (TanIIA) is well known for its protective effect on myocardial disease, and it is know that it also could regulate autophagy in different cells. As this has not yet been shown for hepatocytes, using a mice liver ischemia-reperfusion model, we detected the role of TanIIA in regulating autophagy and the subsequent protective effects on hepatocytes. Our data showed that TanIIA pretreatment could significantly enhance autophagy by the MEK/ERK/mTOR pathway in hepatocytes after liver ischemia-reperfusion, and the enhanced autophagy decreased ROS generation by clearing damaged mitochondria, providing a protective effect on liver ischemia-reperfusion. This protective effect is manifested as reduced serum enzyme levels, reduced liver tissue damage, decreased inflammatory cell infiltration, decreased inflammatory cytokines and reduced hepatocyte apoptosis. In brief, moderate TanIIA utilization might be a potential treatment approach for clinically liver ischemia-reperfusion.