Antioxidant activity has been attributed to the neuroprotective effects of Ginkgo biloba extract EGb-761 on brain disorders including ischemic stroke. It is suggested that oxidative stress implicates in neuron injuries during aging. However, whether or not EGb-761 could be used to treat age-related cerebral ischemia is unclear. In the present study, we directly studied the protective effects of EGb-761 in brain ischemia in the mice with different age. As expected, the recovery from brain damages was impaired in aged mice (24 months) in an animal model of middle cerebral artery occlusion (MCAO). Notably, a 12-month pretreatment of EGb-761 significantly ameliorated the ischemic injury of aged mice in a dose-dependent manner. The decreased stroke severity by EGb-761 was suggested by the reduced infarct volumes and brain edema, accompanied by alleviated oxidative stress. Additionally, we further explored the potential involvement of extra-cellular signal-regulated kinase (ERK) activation by MCAO in aged mice. ERK activation after MCAO was diminished by EGb-761, and this reduction may be mediated through an upregulation of phosphatase PP2A by EGb-761. These observations collectively support that natural antioxidant EGb-761 could be potentially exploited as an effective approach in treating neurological injury during aging.