Unfractionated heparin has long been the conventional anticoagulant for pediatric mechanical circulatory support (MCS). As bivalirudin has gained traction in ventricular assist devices (VAD) management, its role in extracorporeal membrane oxygenation (ECMO) is less well defined. We conducted a retrospective, single-center study investigating the safety and outcomes of bivalirudin, a direct thrombin inhibitor, compared to heparin in a pediatric cardiothoracic intensive care unit (ICU). Outcomes included thrombotic and bleeding events, neurologic complications, survival to decannulation/transplant, and discharge. There were 122 patients for a total of 130 ECMO runs. Bivalirudin was used in 30% of ECMO runs, and bivalirudin demonstrated a 33% risk reduction in major bleeding (95% confidence interval: [−49.9, −16.0], p < 0.01) with fewer circuit component changes per 10 ECMO days (0.64 [0.4–0.7] vs. 2.6 [1.9–5.0], p < 0.01). Extracorporeal membrane oxygenation patients on bivalirudin had greater odds of survival to decannulation (odds ratio [OR]: 3.7 [1.4, 11.5], p = 0.01) and discharge (OR: 3.1 [1.4, 7.2], p < 0.01). The use of bivalirudin for ECMO in the pediatric cardiothoracic ICU population appears safe with fewer major bleeding and thrombotic complications and may be associated with improved survival compared to heparin.