Unfractionated heparin (UFH) is the most used anticoagulant in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO). Its therapeutic levels are monitored using activated partial thromboplastin time ratio (aPTTr) or antifactor Xa (anti-Xa) assay. This was a retrospective, single-center, cohort study where all adult patients with viral etiology respiratory failure requiring VV-ECMO from January 2, 2015 to January 31, 2022 were included. Anticoagulation was monitored using aPTTr (until November 1, 2019) or anti-Xa assay (after November 1, 2019). We compared the accuracy and precision of anticoagulation monitoring tests using time in therapeutic range (TTR) and variance growth rate (VGR), respectively, and their impact on bleeding and thrombotic events (BTEs). A total of 254 patients, 74 in aPTTr and 180 in anti-Xa monitoring groups, were included with a total of 4,992 ECMO-person days. Accuracy was comparable: mean TTR of 47% in aPTTr and 51% in anti-Xa groups (p = 0.28). Antifactor Xa monitoring group demonstrated improved precision with a lower variance (median VGR 0.21 vs. 1.61 in aPTTr, p < 0.05). Secondary outcome of less heparin prescription changes (adjusted rate ratio [RR] = 1.01, p = 0.01), fewer blood transfusions (adjusted RR = 0.78, p < 0.05), and ECMO circuit changes (adjusted RR = 0.68, p < 0.05) were seen with anti-Xa monitoring.