Radioprotective 105kDa protein (RP105) has been reported to produce favorable outcomes in various cardiovascular disorders via a toll‑like receptor4‑dependent or‑independent manner. However, whether RP105 exerts neuroprotective effects against oxygen‑glucose deprivation (OGD)/reoxygenation (OGD/R) injury remains to be elucidated. In the present study, the PC12 neuronal cell line was exposed to 4h of OGD followed by 24h of reoxygenation. Adenoviral vectors encoding RP105 were utilized to upregulate the level of RP105 in PC12 cells prior to OGD/R induction. The results demonstrated that OGD/R reduced the expression of RP105 at the mRNA and protein levels. The overexpression of RP105 significantly reversed OGD/R‑induced neuronal injuries, as demonstrated by the reduced release of lactate dehydrogenate and enhanced cellular viability, in addition to decreased inflammation, apoptosis and reactive oxygen species. The mechanistic evaluations indicated that the neuroprotective functions of RP105 were, in part, a result of activation of the phosphatidylinositol 3‑kinase (PI3K)/protein kinaseB (AKT) pathway. In addition, elimination of the PI3K/AKT axis via the use of a pharmacological inhibitor inhibited the OGD/R‑inhibitory effects induced by the overexpression of RP105. Taken together, RP105 protected PC12 cells from OGD/R injury through promotion of the PI3K/AKT pathway; therefore, the RP105‑PI3K‑AKT axis may provide a novel therapeutic target for the prevention of cerebral ischemia/reperfusion injury.