Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation has been used as a new therapeutic strategy for treating ischemic brain and heart tissues. However, the poor survival rate of transplanted BMSCs in ischemic tissues, due to high levels of reactive oxygen species (ROS), limits the therapeutic efficacy of this approach. Considering that BMSCs survival may greatly enhance the effectiveness of transplantation therapy, the development of effective therapeutics capable of mitigating oxidative stress-induced BMSCs apoptosis is an important unmet clinical need. Here, we characterized for the first time the protective effect of artemisinin, an anti-malaria drug, using an in vitro model of oxidative stress-induced apoptosis in rat BMSCs cultures. We found that artemisinin, at clinically relevant concentrations, improved BMSCs survival by promoting the reduction of ROS production and the concomitant decrease of Caspase 3 activation, LDH release and apoptosis induced by hydrogen peroxide (H2O2). Artemisinin significantly increased extracellular-signal-regulated kinase 1/2 (Erk1/2) phosphorylation, in a concentration- and time-dependent manner. PD98059, a specific inhibitor of the Erk1/2 pathway, blocked Erk1/2 phosphorylation and artemisinin protection. Similarly, downregulation of Erk1/2 by siRNA attenuated the effect of artemisinin, strongly indicating the involvement of the Erk pathway in its protective action. Consistent with this hypothesis, artemisinin increased the phosphorylation of Erk1/2 upstream kinases proto-oncogene c-RAF serine/threonine-protein kinase (c-Raf) and of Erk1/2 downstream targets ribosomal s6 kinase (p90rsk) and cAMP response element binding protein (CREB). In addition, we found that the expression of anti-apoptotic protein B-cell lymphoma 2 protein (BcL-2) was also up-regulated by artemisinin. These studies are a proof of concept of artemisinin’s therapeutic potential to improve in vitro survival of BMSCs exposed to oxidative stress damaging conditions and suggest that artemisinin-mediated protection is likely to occur via the activation of c-Raf-Erk1/2-p90rsk-CREB signaling pathway.