The application of cardiopulmonary bypass (CPB) has significantly advanced cardiovascular surgery. However, CPB-associated brain injury remains a critical complication that affects patient prognosis and quality of life. Overt stroke occurs in approximately 1–5% of cases, while postoperative delirium affects 20–50% of patients, and perioperative neurocognitive disorders are reported in 10–40%, depending on the diagnostic criteria used. This narrative review provides a comprehensive summary of recent research progress on CPB-associated brain injury in cardiac surgery, along with a critical appraisal of the supporting evidence. While the main focus is on adult patients, various pediatric conditions are also discussed. We review the evolution of CPB technology; the classification and clinical burden of brain injury; detailed pathophysiological mechanisms, including hemodynamic injury, microembolism, systemic inflammatory response, and blood–brain barrier disruption; current cerebral protection strategies advances in personalized cerebral perfusion. Furthermore, special consideration is given to genetic susceptibility (such as apolipoprotein E (APOE) polymorphisms), and pediatric cardiac surgery. A systematic screening of high-quality literature from the past five years highlights the challenges that continue to impede clinical translation, despite progress in neuromonitoring and minimally invasive CPB technologies. Future research directions include the application of artificial intelligence and real-time cerebral autoregulation monitoring to support the transition from empirical medicine to precision, individualized cerebral protection.