Previous studies have demonstrated that exercise facilitates recovery from ischemia. However, the mechanisms need to be further elucidated. The current investigation was designed to study the effect of voluntary exercise on cerebral ischemia and discuss possible mechanisms usingmiddle cerebral artery occlusion model. Rats were randomly allocated to three groups: control, middle cerebral artery occlusion, and middle cerebral artery occlusion plus exercise. The middle cerebral artery occlusion plus exercise group was preconditioned by three weeks of voluntary wheel running prior to surgery. The accelerated rotarod test was employed to evaluate motor performance. Infarct volumes were analyzed to detect the neuroprotective effect of voluntary exercise. Brain-derived neurotrophic factor, Bax, Bcl-2, and caspase-3 protein expressions were measured by Western blot. Behavior evaluation showed the middle cerebral artery occlusion plus exercise group achieved significantly longer time on a rotarod than the unexercised group. Additionally, voluntary exercise reduced cerebral infarction and increased brain derived neurotrophic factor expression. Exercise down-regulated the apoptotic Bax/Bcl-2 ratio and caspase-3 protein expression. Results indicate that voluntary wheel running promote hippocampal brain derived neurotrophic factor and inhibit cell apoptosis in ischemia-induced impairment.