Post-translational modification mediated by the ubiquitin proteasome pathway is an important mechanism for organisms to regulate protein levels and functions, which plays an important role in regulating cell homeostasis and survival. Protein post-translational modification is particularly important in cerebral ischemia/reperfusion injury (CI/RI). The structure and function of the ubiquitin proteasome system (UPS) in the area are vulnerable to ischemia, which would eventually lead to delayed apoptotic neuronal death. In-depth exploration of the mechanism of ubiquitinated protein modification after CI/RI will help to develop new therapeutic strategies and drugs. This review aims to briefly summarize the role and mechanism of the UPS in CI/RI models, glutamate excitotoxicity, and cerebral ischemic tolerance. We also discuss the brain protective effects of proteasome modulators in this review. All of views are expected to inspire new ideas for further exploration of the regulatory mechanism of ubiquitinated protein modification after CI/RI.