Thrombosis is a potentially life-threatening complication in veno-arterial extracorporeal membrane oxygenation (ECMO) circuits, which may originate from the drainage cannula due to unfavorable blood flow dynamics. This study aims to numerically investigate the effect of cannula design parameters on local fluid dynamics, and thus thrombosis potential, within ECMO drainage cannulas. A control cannula based on the geometry of a 17 Fr Medtronic drainage cannula concentrically placed in an idealized, rigid-walled geometry of the right atrium and superior and inferior vena cava was numerically modeled. Simulated flow dynamics in the control cannula were systematically compared with 10 unique cannula designs which incorporated changes to side hole diameter, the spacing between side holes, and side hole angles. Local blood velocities, maximum wall shear stress (WSS), and blood residence time were used to predict the risk of thrombosis. Numerical results were experimentally validated using particle image velocimetry. The control cannula exhibited low blood velocities (59 mm/s) at the cannula tip, which may promote thrombosis. Through a reduction in the side hole diameter (2 mm), the spacing between the side holes (3 mm) and alteration in the side hole angle (30° relative to the flow direction), WSS was reduced by 52%, and cannula tip blood velocity was increased by 560% compared to the control cannula. This study suggests that simple geometrical changes can significantly alter the risk of thrombosis in ECMO drainage cannulas.