Extracorporeal membrane oxygenation (ECMO) technology in the field of intense care for children in China has developed rapidly, and it has become a key strategy for the rescue treatment of critically ill children and an advanced extracorporeal life support system. Compared with adults and children, neonatal respiratory disease with ECMO support has the best prognosis, with an average survival rate of 74%. Bleeding and thrombotic events during ECMO are common, morbid, and potentially lethal. Therefore, how to balance the coagulation state is the key to ECMO management. A full-term male infant (2h 5min) was hospitalized for respiratory distress and cyanosis. With a history of premature rupture of membranes (>7 hours) and a birth weight of 3000 g, the patient had Apgar scores of 7, 8, and 9 at 1, 5, and 10 minutes, respectively. This infant has the indication of extracorporeal membrane lung support. After full communication, venoarterial-ECMO was performed, and intravenous infusion of heparin was used for anticoagulation management. We encountered an unreliable heparin monitoring in an infant on ECMO, which considered as heparin resistance. Subsequently, we switched the anticoagulant from heparin to bivalirudin and managed by using multiple laboratory tests including activated clotting time (ACT) and activated partial thromboplastin time. The phenomenon of inconsistent monitoring results occurred later. To help the clinic to adjust the anticoagulation dose accurately, we adopted additional tests such as thrombin-antithrombin complex (TAT) and fibrin/fibrinogen degradation products and applied comparison of thrombela stogram (TEG)-ACT with anticoagulated specimens and bedside non-anticoagulated ACT, then recommended clinicians to use activated partial thromboplastin time combined with TAT. In collaboration with other symptomatic supportive treatments, the ECMO flow was gradually reduced, the respiratory and circulatory functions were stable after reducing the flow rate, there was no bleeding tendency, and the ECMO was finally evacuated. Due to the unique physiological characteristics of newborns, the hemostatic changes differ significantly from those in adults. Precise monitoring of anticoagulation becomes a critical and challenging task. Bivalirudin can be effectively used for anticoagulation management in neonatal ECMO; however, due to its unique characteristics, precise dose adjustment poses a challenge. Selecting the optimal laboratory monitoring indicators is crucial in this regard. In some cases, bedside ACT may not be the optimal anticoagulation monitoring parameter, and when necessary, comparative analysis can be conducted using anticoagulant-sample ACTs such as thrombela stogram-ACT. Traditional markers such as D-dimer/fibrinogen degradation products and newer indicators like TAT can reflect the activation of coagulation and assist in monitoring the anticoagulation effect, especially when there is conflicting information among the monitoring parameters.