Dynamin-related protein 1 (Drp1) regulates mitochondrial fission, it has been proven that inhibition of Drp1 by mdivi-1 improves survival and attenuates cerebral ischemic injury after cardiac arrest. In this study, we compared the effects of Drp1 inhibition with therapeutic hypothermia on post-resuscitation neurologic injury in a rat model of cardiac arrest. Rats were randomized into 4 groups: mdivi-1 treatment group (n = 39), hypothermic group (n = 38), normothermic group (n = 41), and sham group (n = 12). The rats in the mdivi-1 treatment group were received intravenously 1.2 mg/kg of mdivi-1 at 1 minute after the return of spontaneous circulation (ROSC). In rats in hypothermia group, rapid cooling was initiated at 5 minutes after resuscitation, and the core temperature was maintained to 33 ± 0.5°C for 2 hours. The results showed that both Drp1 inhibition and therapeutic hypothermia increased 3-day survival time (allP< 0.05) and improved neurologic function up to 72 hours post cardiac arrest. In addition, both Drp1 inhibition and therapeutic hypothermia decreased cell injury, apoptosis in hippocampal cornu ammonis 1 region and brain mitochondrial dysfunction including adenosine triphosphate production, reactive oxygen species and mitochondrial membrane potential after cardiac arrest. Moreover, therapeutic hypothermia decreased mitochondrial Drp1 expression and mitochondrial fission after cardiac arrest. In conclusion, inhibition of Drp1 has a similar effect to therapeutic hypothermia on neurologic outcome after resuscitation in this cardiac arrest rat model, and the neuroprotective effects of therapeutic hypothermia are associated with inhibition of mitochondrial fission.