ObjectivesExtracorporeal membrane oxygenation (ECMO) plays an important role in providing temporary life support for patients with severe cardiac or pulmonary failure, but requires strict anticoagulation and monitoring. This network meta‐analysis systematically explored the most effective anticoagulation and monitoring strategies for patients receiving ECMO.MethodsMEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched up to January 31, 2023, for studies comparing unfractionated heparin (UFH), argatroban (Arg), bivalirudin (Biv), and/or nafamostat mesylate (NM) in patients receiving ECMO. The primary outcomes included device‐related thrombosis, patient‐related thrombosis, and major bleeding events. The secondary outcomes included ECMO survival, ECMO duration, and in‐hospital mortality.ResultsA total of 2522 patients from 23 trials were included in the study. Biv was associated with a decreased risk of device‐related thrombosis (odd ratio (OR) 0.51, 95% confidence interval (CI): 0.33‐0.84) compared with UFH, whereas NM (OR 2.2, 95% CI: 0.24‐65.0) and Arg (OR 0.92, 95% CI: 0.43‐2.0) did not reduce the risk of device‐related thrombosis compared with UFH. Biv was superior to Arg in decreasing the risk of device‐related thrombosis (OR 0.14, 95% CI: 0.03‐0.51). Biv reduced the risk of patient‐related thrombosis compared with UFH (OR 0.44, 95% CI: 0.18‐0.85); NM (OR 0.65, 95% CI: 0.14‐3.3) and Arg (OR 3.1, 95% CI: 0.94‐12.0) did not decrease risk of patient‐related thrombosis compared with UFH. No significant difference was observed in the risk of major bleeding between three alternatives and UFH: Biv (OR 0.54, 95% CI: 0.23‐1.3), Arg (OR 1.3, 95% CI: 0.34‐5.8), and NM (OR 0.60, 95% CI: 0.13‐2.6). NM showed a reduced risk of in‐hospital mortality compared with UFH (OR 0.27, 95% CI: 0.091‐0.77), whereas Arg (OR 0.43, 95% CI: 0.15‐1.2) and Biv (OR 0.75, 95% CI: 0.52‐1.1) did not decrease risk of in‐hospital mortality.ConclusionsCompared with UFH and Arg, Biv reduces the risk of thrombosis and appears to be a better choice for patients requiring ECMO. NM was associated with a reduced risk of in‐hospital mortality.