The aim of the present study was to investigate the neuroprotective effects of bone marrow-derived endothelial progenitor cell (EPC) transplantation against cerebral ischemia/reperfusion (I/R) injury in rats and to delineate the possible underlying mechanisms. Cerebral I/R injury was established by 2 h of middle cerebral artery occlusion (MCAO) followed by reperfusion for 24 h. EPCs were isolated from bone marrow of the donor rats, grown in conditioned medium, and characterized by flow cytometry analysis of several surface markers. Labeled EPCs (106 cells) were infused into rats at the onset of reperfusion and 12 h after reperfusion via the tail vein. Infarct volume was assessed at 24 h after reperfusion by using triphenyltetrazolium chloride (TTC) staining. The expression of cell apoptosis-related proteins including Bcl-2 and Bax was determined by western blot analysis, and the activity of caspase-3 was also measured. We evaluated the activities of some antioxidative enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), the non-enzymatic scavenger glutathione (GSH) and detected the content of malondialdehyde (MDA) in the ischemic penumbra. Moreover, the expression of nuclear factor-κB (NF-κB) in the ischemic regions of rats was examined by immunohistochemical staining and western blot analysis. The results showed that transplantation of EPCs significantly reduced the cerebral infarct volume, decreased caspase-3 activity, upregulated Bcl-2 expression, and downregulated the expression of Bax and NF-κB. Furthermore, reduced levels of MDA, significantly elevated activities of SOD and GSH as well as GSH-PX were also found in I/R rats transplanted with EPCs. Collectively, our data demonstrated that transplantation of bone marrow-derived EPCs exerts potent neuroprotective functions against cerebral I/R injury in rats, and the protective effects may be associated with its antioxidative and anti-apoptotic properties.