Some epidemiological studies concerning gender differences in Alzheimer's disease (AD) support the higher prevalence and incidence of AD in women, while most studies using animal models of aging have included only male subjects. It is still uncommon for aged males and females to be compared in the same study. In the present study, we investigated how age and gender influence the excitotoxic neurodegeneration by treating C57BL/6 mice (aged females and males as well as adult females and males) with kainic acid (KA) intranasally. Clinical signs, behavioural changes, pathological changes and astrocyte proliferation were tested; and the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were measured after KA treatment. The results showed that aged female mice were more sensitive to KA-induced excitotoxicity as demonstrated by severer seizure activity, increased locomotion and rearing in open-field test, prominent hippocampal neuronal damage, enhanced astrocyte proliferation compared with aged males, adult females and adult male mice. In addition, higher BDNF level in hippocampus of aged female mice was observed. These results denote the disparity of aging and gender in KA-induced hippocampal neurodegeneration and aged female mice are more sensitive to the excitotoxicity.