The neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh Rehmannia roots, on the senescent mice induced by D-galactose were assessed. The mice subcutaneously injected with catalpol (5 or 10 mg/kg, 2 weeks, from fifth week) showed significantly improved learning and memory ability in Morris water maze test compared with d-galactose treated mice (150 mg/kg, 6 weeks). We further investigated the mechanism involved in the neuroprotective effects of catalpol on the mice brain tissue. The results showed that catalpol increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the malondialdehyde (MDA) level, elevated the activities of Na+ -K+ ATPase and Ca2+ -Mg2+ ATPase on the cerebral cortex and hippocampus of d-galactose treated mouse. All the data suggested that catalpol had the potential to be a useful cognitive impairment treatment, and its beneficial effects may be partly mediated via enhancing endogenous antioxidant enzymatic activities and inhibiting free radical generation.