Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and the TandemHeart left ventricular (LV) assist device are increasingly employed as mechanical circulatory support devices during acute LV injury. We examined the effects of right atrial to femoral artery (RA–FA; VA-ECMO) bypass versus left atrial to femoral artery (LA–FA; TandemHeart) bypass using a centrifugal pump (Cardiac Assist Inc, Pittsburgh, PA) on LV hemodynamics in a swine model of acute LV injury. In eight male swine, the RA–FA bypass group employed a 21 Fr inflow cannula in the right atrial (RA) and a 17 Fr FA outflow cannula. The LA–FA bypass group employed a 21 Fr inflow cannula in the LA and a 17 Fr FA outflow cannula. Both pump configurations were activated at 3,500 rotations per minute (RPMs) followed by balloon angioplasty-mediated occlusion of the left circumflex (LCx) artery. After 30 minutes of LCx occlusion, RPMs through the centrifugal pump were increased from 3,500, 5,500 then to a maximum at 7,500 RPMs. At 7,500 RPMs, RA–FA and LA–FA bypass generated 3.5 ± 0.1 and 3.6 ± 0.2 liters/minute (LPM) of flow, respectively. At maximum flow, RA unloading increased LV end-systolic pressure and estimated wall stress, whereas LA unloading reduced LV end-diastolic pressure, end-diastolic volume, and native stroke volume without changing estimated wall stress. Veno-arterial extracorporeal membrane oxygenation acutely increases mean arterial pressure (MAP) without unloading the LV, whereas the TandemHeart maintains MAP and unloads the LV. These findings indicate that RA versus LA cannulation for circulatory support have distinct acute hemodynamic effects on the LV.