Erythropoietin (EPO) has been shown to be a key cytokine in the production of erythrocytes from erythroblasts. Recently, attempts have been made to adopt EPO as a drug target for neuroprotection in selected neurological pathologies. In the current study, a novel EPO-derived peptide which mimics the weak binding site of EPO to its receptor (MK-X) was generated. Experimental results demonstrated that MK-X was able to ameliorate neuronal death due to reactive oxygen species and conditions of oxidative stress similar to EPO. In addition, MK-X induced long-lasting Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Akt activation. Furthermore, treatment with inhibitors of ERK1/2 and Akt abolished the neuroprotective effect of MK-X. Unlike EPO, however, MK-X did not induce cellular proliferation. Collectively, the results of the current study suggested that MK-X may be useful as a novel neuroprotective reagent.