Cerebral ischemia reperfusion (I/R) could cause cognitive impairment, accompanied by free radical generation and acetylcholinesterase (AChE) activity exaltation. In our study, we evaluated the effects of mangiferin (MGN) on cognitive performance in I/R-induced mice. Cognitive performance was assessed using Morris water maze test (MWMT), step-down passive avoidance test (SDPAT), novel object recongnition task (NORT) and open-field test (OFT). Meanwhile, the parameters of oxidative stress (ROS) were the activity of superoxidedismutase (SOD), catalase (CAT), the level of glutathione (GSH), and malondialdehyde (MDA). Besides, due to acetylcholine esterase (AChE) as an important neurotransmitter enzyme in hippocampus playing a vital role in cognitive performance, it activity was determined to assess the influence on congnitive deficits. Cerebral I/R mice showed a severe deficit in memory associated with elevated ROS, MDA levels and AChE activity, attenuated SOD, CAT and GSH activity. However, MGN treatment improved cognitive performance and resulted in a significant reduction in ROS, MDA levels and AChE activity and elevation in SOD, CAT and GSH activity. This study demonstrated that MGN may be beneficial to ameliorate learning and memory deficits induced by I/R through inhibition oxidative stress and AChE activity especially in hippocampus and cerebral cortex of mice brain.