Technical advances in extracorporeal membrane oxygenation (ECMO) have increased the number of cases that maintain longer duration. Long-term use of ECMO results in ECMO-related complications. Anticipation of the life-threatening mechanical complications and their management are critical for safe ECMO. In this study, we analyzed the incidence, nature, and risk factors of life-threatening mechanical complications during ECMO support. Furthermore, we presented our bedside algorithms to manage catastrophic ECMO complications. Data from 549 patients who underwent ECMO between December 2008 and December 2018 were retrospectively analyzed. The incidence of all life-threatening mechanical complications was 4.0%. Accidental decannulation (1.3%) was most common, followed by abrupt falling circuit flows (1.1%), pump failure (1.1%), circuit rupture (0.4%), and air in circuit (0.2%). Most (90.9%) of life-threatening events required circuit and cannula change, while 9.1% required vein collapse relief procedure. There was no death related to the event; however, six (27.3%) died during ECMO due to the underlying disease for which ECMO was required, and three (13.6%) died after weaning from ECMO. Multivariate regression analysis showed that awake ECMO and long-term ECMO support were significantly associated with life-threatening mechanical complications (p < 0.01). Our algorithm safely managed catastrophic ECMO problems without event-related deaths.