Objective To investigate whether the antioxidation and the regulation on the Extracellular Regulated Protein Kinases (ERK) signaling pathway are involved in the protective effects of blueberry on central nervous system. Methods 30 Senescence-accelerated mice prone 8 (SAMP8) mice were divided into three groups and treated with normal diet, blueberry extracts (200 mg/kg·bw/day) and cyaniding-3-O-galactoside (Cy-3-GAL) (50 mg/kg·bw/day) from blueberry for 8 weeks. 10 SAMR1 mice were set as control group. The capacity of spatial memory was assessed by Passive avoidance task and Morris water maze. Histological analyses on hippocampus were completed. Malondialdehyde (MDA) levels, Superoxide Dismutase (SOD) activity and the expression of ERK were detected. Results Both Cy-3-GAL and blueberry extracts were shown effective functions to relieve cellular injury, improve hippocampal neurons survival and inhibit the pyramidal cell layer damage. Cy-3-GAL and blueberry extracts also increased SOD activity and reduced MDA content in brain tissues and plasma, and increased hippocampal phosphorylated ERK (p-ERK) expression in SAMP8 mice. Further more, the passive avoidance task test showed that both the latency time and the number of errors were improved by Cy-3-GAL treatment, and the Morris Water Maze test showed significant decreases of latency were detected by Cy-3-GAL and blueberry extracts treatment on day 4. Conclusion Blueberry extracts may reverse the declines of cognitive and behavioral function in the ageing process through several pathways, including enhancing the capacity of antioxidation, altering stress signaling. Cy-3-GAL may be an important active ingredient for these biological effects.