One of the major problems influencing the therapeutic efficacy of stem cell therapy is the poor cell survival following transplantation. This is partly attributed to insufficient resistance of transplanted stem cells to oxidative and inflammatory stresses at the injured sites. In the current study, we demonstrated the pivotal role of antioxidant levels in human umbilical cord mesenchymal stem cells (hUCMSCs) dynamic in vitro anti-stress abilities against lipopolysaccharide (LPS)/H2O2 intoxication and in vivo therapeutic efficacy in a murine acute liver failure model induced by D-galactosamine/LPS (Gal/LPS) by either reducing the antioxidant levels with diethyl maleate (DEM) or increasing antioxidant levels with edaravone. Both the anti- and pro-oxidant treatments dramatically influenced the survival, apoptosis, and reactive oxygen species (ROS) production of hUCMSCs through the MAPK-PKC-Nrf2 pathway in vitro. When compared with untreated and DEM-treated cells, edaravone-treated hUCMSCs rescued NOD/SCID mice from Gal/LPS-induced death, significantly improved hepatic functions and promoted host liver regeneration. These effects were probably from increased stem cell homing, promoted proliferation, decreased apoptosis and enhanced secretion of hepatocyte growth factor (HGF) under hepatic stress environment. In conclusion, elevating levels of antioxidants in hUCMSCs with edaravone can significantly influence their hepatic tissue repair capacity.