Venovenous extracorporeal membrane oxygenation (ECMO) is used for support in refractory severe respiratory failure. Venous drainage and return are accomplished through cannulation of patient’s major veins, typically on the neck and/or the groins. Cannulation configuration may affect treatment efficiency, but it remains unclear if any strategy is superior. Computational fluid dynamics was used to evaluate and compare the femoro-femoral (FF), jugulo-femoral (JF), and femoro-jugular (FJ) cannulation configurations. Cannulae were modelled in an adult patient-averaged geometry of the right atrium and venae cavae. Large eddy simulations were performed at ECMO flow rates of 2–6 L/min. Time-averaged flow data was collected for assessment of flow parameters associated with clinical efficiency. FF cannulation showed lower recirculation than FJ and JF. Negative pressures in the inferior vena cava, associated with an increased risk of vascular collapse, were more pronounced in the FF configuration. Additionally, wall shear stresses exceeded physiological levels even at low flow rates and increased with higher flow, increasing the risk of blood trauma. Shear stress varied significantly inside the drainage cannula, highlighting sensitivity to local flow dynamics. This study advances our understanding of three common VV ECMO configurations, giving insights to improve efficiency and address clinical challenges.