Antithrombin (AT) depletion is common in critical illness, and during venovenous extracorporeal membrane oxygenation (VV ECMO), blood–surface interactions further amplify coagulation and inflammation cascades. The prognostic value of baseline AT activity complications at ECMO initiation remains unclear. We conducted a single-center retrospective cohort study of adults receiving VV ECMO (2013–2023) to investigate associations between baseline AT activity and bleeding and thrombosis risk. Clinical outcomes included computed tomography (CT)-confirmed ischemic, thrombotic, and bleeding complications and death during ECMO. Analyses included logistic regression, cause-specific Cox models, and unsupervised methods. Among 734 patients, 64% were AT-deficient (< 77%). Antithrombin activity inversely correlated with inflammatory markers. Ischemic complications were more frequent in AT-deficient patients (7.6% vs. 1.9%, p < 0.01), while thrombotic and bleeding rates were similar. Antithrombin activity predicted reduced odds of ischemic events (odds ratio [OR]: 0.97 per 1% increase, 95% confidence interval [CI]: 0.95, 0.98), with an optimal AT threshold of 49 for prediction of ischemic complications (area under the curve [AUC] = 0.74). Three subphenotypes were identified: a consumptive phenotype with markedly reduced AT activity, which carried the highest burden of ischemic complications and mortality. Baseline AT activity and inflammatory status may identify VV ECMO patients at increased risk of ischemia and death, particularly those with a consumptive profile.