Cardiopulmonary bypass (CPB) is one of the most groundbreaking medical innovations in history, enabling safe and effective heart surgery by temporarily replacing the function of the heart and lungs. This review starts with ancient concepts of cardiopulmonary function and then traces the evolution of CPB through important physiological and anatomical discoveries, culminating in the development of the modern heart–lung machine. In addition to examining the contributions of significant figures like Galen, Ibn al-Nafis, William Harvey, and John Gibbon, we also examine the ethical and technical challenges faced in the early days of open heart surgery. Modern developments are also discussed, such as miniature extracorporeal systems, off-pump surgical techniques, and the increasing importance of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS), while the evolving role of perfusionists in diverse cardiac teams and the variations in global access to CPB technology are also given special attention. We look at recent advancements in CPB, including customized methods, nanotechnology, artificial intelligence-guided perfusion, and organ-on-chip testing, emphasizing CPB’s enduring significance as a technological milestone and a living example of the cooperation of science, medicine, and human inventiveness because it bridges the gap between the past and the future.