The potential of three natural flavonols (galangin, kaempferol and myricetin) to protect against D-galactose induced cognitive impairment in mice was investigated. After 8 weeks treatment, the mice were assessed by behavioural tests. The levels of oxidative stress, the amount of Na+, K+-ATPase and extracellular signal-regulated kinases (ERK)-cyclic AMP response element binding protein (CREB) signaling pathway in hippocampus were also analysed. It was found that all the three dietary flavonols could ameliorate the oxidative stress, enhance the activity of Na+,K+-ATPase and regulate the expression of ERK-CREB pathway in mice. However, only kaempferol and myricetin could significantly improve the learning and memory capability when compared with D-galactose model. Our results suggest that the presence of hydroxyl groups in the B ring of flavonols may have contribution to the neuroprotective activity.