Ischemia/reperfusion (I/R) injury remains a major problem in liver transplantation. I/R causes inflammatory cytokine release, apoptosis, and necrosis. Bone marrow-mesenchymal stem cells (BM-MSCs) can differentiate into hepatocytes in vivo, and differentiation further increases when hepatocytes are damaged. Exosomes are important mediators of cellular connections. Recently, exosomes of hepatocytes have been shown to play a pivotal role in inhibiting hepatocyte apoptosis and promoting hepatocyte regeneration. Therefore, we induced MSCs to differentiate into hepatocyte-like cells and extracted their exosomes; we then injected the exosomes into a mouse hepatic I/R model through the tail vein. Simultaneously, CoCl2 was used to mimic I/R in vitro. Our data indicated that in vivo, mesenchymal stem cell-derived hepatocyte-like cell exosomes (MSC-Heps-Exo) effectively relieve hepatic I/R damage, reduce hepatocyte apoptosis, and decrease liver enzyme levels. Consistent with the in vivo results, the in vitro experiments confirmed that exosomes effectively increased hepatocyte tolerance to ischemia and reduced hepatocyte apoptosis. We thus found that autophagy enhancement may be the mechanism by which exosomes protect the liver from I/R injury. These results indicate that exosomes play a protective role in hepatic I/R, and that the use of BM-MSCs for hepatocyte induction and exosome extraction may provide a new clinical treatment method through bioengineering.