Previous studies suggested that contact pathway factors drive thrombosis in mechanical circulation. We used a rabbit model of veno-arterial extracorporeal circulation (VA-ECMO) to evaluate the role of factors XI and XII in ECMO-associated thrombosis and organ damage. Factors XI and XII were depleted using established antisense oligonucleotides (ASO) prior to placement on a blood-primed VA-ECMO circuit. Decreasing FXII or FXI to <5% of baseline activity significantly prolonged ECMO circuit lifespan, limited the development of coagulopathy, and prevented fibrinogen consumption. Histological analyses suggested that FXII depletion mitigated interstitial pulmonary edema and hemorrhage whereas heparin and FXI depletion did not. Neither FXI nor FXII depletion were associated with significant hemorrhage in other organs. In vitro analyses showed that membrane oxygenator fibers (MOFs) alone are capable of driving significant thrombin generation in a FXII and FXI-dependent manner. MOFs also augment thrombin generation triggered by low (1 pM) or high (5 pM) tissue factor (TF) concentrations. However, only FXI elimination completely prevented the increase in thrombin generation driven by MOFs, suggesting MOFs augment thrombin-mediated FXI activation. Together, these results suggest that therapies targeting FXII or FXI limit thromboembolic complications associated with ECMO. Further studies are needed to determine the contexts where targeting FXI and FXII, either alone or in combination, would be most beneficial in ECMO. Further studies are also needed to determine the potential mechanisms coupling FXII to end organ damage in ECMO.