Ischemia stroke is a disease with high morbidity and mortality. Cistanche deserticola polysaccharides (CDP) possess a wide range of beneficial effects, including hepatoprotection and immune homeostasis. As far as we know, the protective effect of CDP on neurons injured by oxygen-glucose deprivation/reperfusion (OGD/RP) has not been investigated. In this study, OGD/RP injured a PC12 cell model. Briefly, CDP (0.05, 0.5 and 5 μg/ml) was administered before reperfusion. The protective effect of CDP was then evaluated on the basis of cell viability, lactate dehydrogenase (LDH) leakage, [Ca²⁺]_i, mitochondrial membrane potential (MMP)and cell apoptosis, and redox status after reperfusion was evaluated by assaying reactive oxygen species (ROS), catalase (CAT), glutathione peroxidase (GSH-Px) and total antioxidant capacity. Basing on the fact that Parkinson’s disease-associated protein DJ-1 participates in endogenous antioxidation and performs neuroprotective effects after ischemia stroke, we investigated the interaction between CDP and DJ-1. DJ-1 expression was detected through ELISA and Western blot analysis, and the translocation of DJ-1 was evaluated through immunofluorescence. Result showed that CDP (0.05, 0.5 and 5 μg/ml) attenuated PC12 cell death, preserved MMP and calcium homeostasis; inhibited oxidative stress and decreased cell apoptosis. Moreover, CDP (5 μg/ml) markedly stimulated DJ-1 secretion and expression. Overall, the results suggested that CDP exerts neuroprotective effect against OGD/RP-induced injury by inhibiting oxidative stress and regulating the DJ-1 pathway.