Electrocardiogram (ECG)—synchronized pulsatile veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is a recent development in extracorporeal therapy for patients with severe cardiogenic shock. Although preclinical studies have shown benefits of pulsatile flow relative to continuous ECMO flow, none have explored the effects of the timing of ECMO pulses with respect to the cardiac cycle and its possible implications on ECMO complications. This study aimed to develop a computational fluid dynamics (CFD) model of V-A ECMO in a patient-specific human aorta and evaluate the effect of ECMO timing on cardiac unloading, surplus hemodynamic energy delivery, and mixing zone position. Using direct flow measurements from cardiogenic shock patients and an ECMO device, the model revealed that maximal left ventricular (LV) unloading occurred when the ECMO pulse was in early diastole (35–40% from LV peak systolic flow). Maximum surplus hemodynamic energy transmission to aortic branches occurred at 20% from LV peak systolic flow. This indicates a trade-off between heart afterload and hemodynamic energy delivery in selecting ECMO pulse timing. The mixing zone was primarily located in the aortic arch across timing configurations. Therefore, selecting ECMO pulse timing is crucial to maximizing the benefits of pulsatile flow in V-A ECMO treatment.