A critical step of MSCs therapy is dependent on its ability to migrate into the sites of injury, so various approaches have been introduced to boost the migratory ability of MSCs. PGE2 is the major prostaglandin generated by COX enzymes and has been implicated in inflammatory response. Evidence indicates that PGE2 can facilitate MSCs migration. Further exploration of the underlying molecular mechanism participating in the promigratory ability of PGE2 may provide a novel strategy to improve MSC transplantation efficacy. In this study, our findings suggested that EP2 prostanoid receptor promotes MSCs migration through activation of FAK and ERK1/2 pathways. Furthermore, MSCs migration induced by PGE2 was blunted by FAK or ERK1/2 inhibitors. EP2-mediated MSCs migration depends on the activation of FAK and ERK1/2. However, the current study did not investigate the migration of MSCs over a blood vessel endothelial barrier. In conclusion, our findings reveal EP2-mediated FAK and ERK1/2 activation was essential for MSCs migration induced by PGE2, indicating that activation of EP2 receptor and FAK/ERK pathways may be a promising strategy to accelerate homing efficiency of MSCs, which in turn enhances therapeutic potential of MSCs transplantation.