Aerobic exercise is known to increase expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and to improve cognitive function. The inhibition of GABAergic synapses enhances hippocampal plasticity as well as learning and memory. The objective of the present study was to examine the interactive effect of low-level GABAA receptor inhibition and exercise on behavior tests (cognitive function and locomotor activity), expression of BDNF and epigenetic regulations including the activity levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in the hippocampus. ICR mice were divided into two groups: those who did not participate in exercise and those who participated in exercise. Each group was subdivided into two other groups: the one who received vehicle and the one who received GABAA receptor antagonist, bicucullin. We administered saline or bicuculline intraperitoneally to the mice at a non-epileptic dose of 0.25 mg/kg, whereas the mice were exercised on a treadmill for approximately 1 h a day, 5 days a week for 4 weeks. Novel-object recognition test and locomotor activity were assessed at a rest day approximately 4 days before the euthanasia. The mice were euthanized 4 h after the last exercise session. Aerobic exercise for 4 weeks increased mRNA and protein expression of BDNF in the hippocampus, accompanied by enhanced HAT activity. Alternatively, bicuculline administration increased HDAC activity in the hippocampus. Furthermore, exercise in the presence of bicuculline administration increased locomotor activity, indicating that exercise combined with low-level GABAA receptor inhibition potentiated the activity of the mice. Altogether, the present study suggested that exercise beneficially contributes to neuroprotection in the hippocampus accompanied by the up-regulation of BDNF expression and epigenetic regulation, whereas the chronic inhibition of GABAA receptor potentiates exercise-induced behavioral activity.