Acute brain injury (ABI), including stroke and traumatic brain injury, which accounts for a heavy burden of morbidity and mortality, results in a great loss of productive life and serious health problem worldwide. To improve patients' survival and ameliorate their outcome, effective clinical treatment strategies and new therapeutic targets are urgently needed. Novel therapeutic strategies, especially about stem cell therapy and various targets to enhance the therapeutic effects of stem cell therapy, are emerging all the time. Irisin is a myokine released from cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5). This myokine is closely related to metabolism and neural stem cell differentiation, and it gained attention in recent years. Recent studies reported that FNDC5/Irisin may play a key role in brain injury, for it might be a powerful agent mediating the neural cell response and stem cell therapy. This review aims at understanding the newly discovered myokine “Irisin,” discussing the potential role and mechanisms of Irisin in ABI, and shedding light on its potential application in stem cell therapy. Furthermore, we propose that Irisin could be a novel protagonist in the treatment and prevention of ABI.