Stroke is the main cause of adult disability in developing countries. There is a need for identifying new signalling pathways involved in stroke pathogenesis to discover potential therapeutic strategies for stroke. We previously found that the E3 ubiquitin ligase APC/C-Cdh1 promotes neurogenesis, proliferation, and neuronal survival, which are essential events for brain repair after stroke. APC-Cdh1 also regulates protein levels of the dendrite stabilizer Rock2. Thus, the APC/C-Cdh1-Rock2 axis modulates dendrite elongation and synaptogenesis. However, whether Cdh1 plays a role in stroke remains unknown.We used both, in vitro (ischemia/reoxygenation, I/R) and in vivo (middle cerebral artery occlusion, MCAO) models of ischemia in mice lacking Cdh1 in the central nervous system (Cdh1-KO) and WT mice.Cdh1 loss promoted Rock2 stabilization and neuronal susceptibility to I/R, which was prevented by genetic and pharmacological inhibition of Rock2. In vivo studies revealed that, despite initial (24 hours) infarct volume was similar in both genotypes, Rock2 accumulated and neuronal death increased in the peri-infarct area of Cdh1-KO mice, at 7 days after MCAO. Interestingly, neurological and motor tests revealed impaired functional recovery in Cdh1-KO mice.We identify the APC/C-Cdh1-Rock2 axis as a key modulator of the neuronal response to ischemia, making Cdh1 and Rock2 potential molecular targets for stroke treatment.Funded by Instituto de Salud Carlos III (PI21/00727, RD21/0006/0005, RD21/0006/0020, cofunded by the European Union), FEDER, and Bodegas R. López de Heredia Viña Tondonia.