The use of extracorporeal circulation for cardiac surgery and extracorporeal life support poses tremendous challenges to the hemostatic equilibrium given its diametric tendency to trigger hyper‐ and hypocoagulopathy. The necessity of anticoagulant therapy to counteract the hemostatic activation by the extracorporeal circuitry compounded by unfavorable patient and surgical factors significantly increase the risk of catastrophic bleeding in patients who require extracorporeal circulation. Preoperative measures, such as stratification of high‐risk bleeding patients, and optimization of the modifiable variables, including anemia and thrombocytopenia, provide a crude estimation of the likelihood and may modify the risk of catastrophic bleeding. The anticipation for catastrophic bleeding subsequently prompts the appropriate preparation for potential resuscitation and massive transfusion. Equally important is intraoperative prevention with the prophylactic application of tranexamic acid, an antifibrinolytic agent that has promising benefits in reduction of blood loss and transfusion. In the event of uncontrolled catastrophic bleeding despite preemptive strategies, all effort must be centered on regaining hemostasis through surgical control and damage control resuscitation to protect against worsening coagulopathy and end organ failure. When control of bleeding is reinstated, management should shift focus from systemic therapy to targeted hemostatic therapy aimed at the potential culprits of coagulopathy as identified by point of care hemostatic testing. This review article outlines the strategies to appropriately intervene using prediction, prevention, preparation, protection, and promotion of hemostasis in managing catastrophic bleeding in extracorporeal circulation.