One of the major challenges in emergency medicine is out-of-hospital cardiac arrest (OHCA). Every year, about 53–62/100000 people worldwide suffer an out-of-hospital cardiac arrest with serious consequences, whereas persistent brain injury is a major cause of morbidity and mortality of those surviving a cardiac arrest. Today, only few and insufficient strategies are known to limit neurological damage of ischemia and reperfusion injury. The aim of the present study was to investigate whether teriflunomide, an approved drug for treatment of relapsing-remitting-multiple-sclerosis, exerts a protective effect on brain cells in an in vitro model of ischemia. Therefore, organotypic slice cultures from rat hippocampus and cerebellum were exposed to oxygen-glucose-deprivation and subsequently treated with teriflunomide. The administration of teriflunomide in the reperfusion time on both hippocampal and cerebellar slice cultures significantly decreased the amount of detectable propidium iodide signal compared with an untreated culture, indicating that more cells survive after oxygen-glucose-deprivation. However, hippocampal slice cultures showed a higher vulnerability to ischemic conditions and a more sensitive response to teriflunomide compared with cerebellar slice cultures. Our study suggests that teriflunomide, applied as a post-treatment after an oxygen-glucose-deprivation, has a protective effect on hippocampal and cerebellar cells in organotypic slice cultures of rats. All procedures were conducted under established standards of the German federal state of North Rhine Westphalia, in accordance with the European Communities Council Directive 2010/63/EU on the protection of animals used for scientific purposes.