Stroke is a leading cause of death and disability worldwide. Obesity is an important risk factor for stroke, while exercise can reduce the incidence and the mortality associated with stroke. However, little is known about the mechanisms underlying the effect of obesity and exercise on the pathogenesis of stroke. Recent studies have highlighted the role of exercise-induced myokines in mediating the beneficial effect of exercise. Among the discovered myokines, irisin has been shown to exert neuroprotective role in brain disorders, such as Alzheimer\'s disease. In this study, the effect of exercise and exercise-induced myokine irisin was examined in ischemic stroke with obesity. Mice fed a high-fat diet (HFD) were on treadmill exercise and then subjected to transient middle cerebral artery occlusion (MCAO). The results showed that exercise significantly reduced infarct size and increased survival rate compared to the HFD group. Inflammatory and apoptotic markers induced by HFD was also reversed in exercised group, while exercise increased tight junction factors. In addition, plasma irisin concentration and irisin expression in muscle and brain were all increased by exercise. In mice deficient in FNDC5, the precursor of irisin, MCAO-induced ischemic stroke was exacerbated, with aggravated inflammation and tight junction markers compared to control mice. In conclusion, exercise and exercise-induced myokine irisin are suggested to exert protective effects on ischemic stroke.