Mitochondria are highly dynamic organelles which are joined by mitochondrial fusion and divided by mitochondrial fission. The balance of mitochondrial fusion and fission plays a critical role in maintaining the normal function of neurons, of which the processes are both mediated by several proteins activated by external stimulation. Cerebral ischemia-reperfusion (I/R) injury can disrupt the balance of mitochondrial fusion and fission through regulating the expression and post-translation modification of fusion- and fission-related proteins, thereby destroying homeostasis of the intracellular environment and causing neuronal death. Furthermore, human intervention in fusion- and fission-related proteins can influence the function of neurons and change the outcomes of cerebral I/R injury. In recent years, researchers have found that mitochondrial dysfunction was one of the main factors involved in I/R, and mitochondria is an attractive target in I/R neuroprotection. Therefore, mitochondrial-targeted therapy of the nervous system for I/R gradually started from basic study to clinical application. In the present review, we highlight recent progress in mitochondria fusion and fission in neuronal death induced by cerebral I/R to help understanding the regulatory factors and signaling networks of aberrant mitochondrial fusion and fission contributing to neuronal death during I/R, as well as the potential neuroprotective therapeutics targeting mitochondrial dynamics, which may help clinical treatment and development of relevant dugs.