The aim of this study is to elucidate the molecular mechanism of Galanin receptors type 2(GALR2)which involved in regulation of oxidative stress in the hippocampus. We used real-time PCR technique to investigate the change of GALR2 expression in hippocampus of piglets and hippocampal neurons of rats, based on the successfully constructed oxidative stress model. Real-time PCR, Western blotting and transmission electron microscopy were used to further explore the relationship between the signal pathway mediated by GALR2 and autophagy. The results showed that the transcription levels of GALR2 were up-regulated in the hippocampus of oxidative stressed piglets and rat hippocampal neurons compared with the control group (P<0.01; P<0.05). At the same time, the transcription levels of LC3, ATG5 and Beclin-1 in oxidative stressed neurons were up-regulated (P<0.05; P<0.05; P<0.01). Correlation analysis showed that GALR2 was positively correlated with LC3, ATG5 and Beclin-1 (P<0.05; P<0.05; P<0.01). The treatment with M871, a specific inhibitor of GALR2, decreased the activity of hippocampal neurons under oxidative stress (P<0.01) , increased the number of autophagosomes (P<0.01) and transcription levels of LC3, Beclin-1 and ATG5(P<0.01) , and increased the ratio of LC3-Ⅱ/actin and P62 protein level (P<0.05) , showing that the autophagy of hippocampal neurons, which was up-regulated by oxidative stress, was inhibited with the inhibition of GALR2 expression, thus weakening the resistance to oxidative damage and decreasing the viability of neurons. Simultaneously, M871 treatment also decreased the up-regulated protein level (P<0.01) and the phosphorylation level of JNK (P<0.05) in oxidative stressed neurons, indicating that JNK is the downstream target enzyme of GALR2 in hippocampal neurons under oxidative stress. However, treatment with JNK specific inhibitor SP600125 lowered the ratio of LC3-II/actin, which was up-regulated by oxidative stress (P<0.01), showing the inhibition of JNK blocks the activation of the autophagic pathway by an up-regulated GALR2 in neurons. To sum up: under oxidative stress, the up-regulated GALR2 in hippocampal neurons can activate the autophagy pathway by up-regulating JNK signal pathway, thus attenuate oxidative stress injury and protect neurons.