The purpose of this study was to determine the effectiveness of the systemic administration of high dose erythropoietin (EPO) in a 6‑hydroxydopamine (6‑OHDA)‑ induced rat model. Rats were divided into 7 groups. Groups 1‑4 were administered daily EPO doses of 0; 2,500; 5,000 and 10,000 U/kg via intraperitoneal injection (i.p.) for 5 days. The EPO concentration in cerebrospinal fluid (CSF) was determined by enzyme‑linked immunosorbent assay (ELISA) and western blot analysis. The dose of 10,000 U/kg was then selected for subsequent experiments. In group 5, rats received saline via medial forebrain bundle (MFB). In group 6, rats received 6‑OHDA via MFB. In group 7, an EPO concentration of 10,000 U/kg was constantly administered i.p. for 5 days to rats prior to 6‑OHDA injection via MFB. Behavioral analysis was performed for groups 5‑7 by rat rotation tests. The number of tyrosine hydroxylase (TH)‑immunopositive cells in the substantia nigra (SN) was measured by immuno-cyto-chemistry. The activation of c‑Jun N‑terminal kinase (JNK), extracellular signal‑regulated kinase (ERK), p38 mitogen‑activated protein kinases (MAPKs) and caspase‑3 signaling in rats were analyzed using western blotting. The results showed that there was a significant increase in EPO levels in the CSF in 10,000 U/kg group compared with the 2,500 and 5,000 U/kg groups (P<0.01). Significantly fewer rotational counts were obtained in rats that were pretreated with EPO compared with saline‑pretreated 6‑OHDA‑lesioned rats (P<0.001). The dopaminergic neurons in the 6‑OHDA‑lesioned SN were also increased in the EPO‑pretreated rats when compared with control rats (P<0.01). Western blot analysis revealed that EPO inhibited the 6‑OHDA‑induced activation of JNK, ERK, p38 MAPK and caspase‑3 signaling in the rat model. In conclusion, systemic administration of a high dose of EPO exerted neuroprotective effects in reversing behavioral deficits associated with Parkinson's disease and prevented loss of the dopaminergic neurons through the MAPK pathway.