The interaction between primary left ventricular output and Veno-arterial extracorporeal membrane pulmonary oxygenation (VA ECMO) flow may impede the perfusion of aortic vessels with hyperoxic blood, leading to differential oxygenation. ECMO return cannula design significantly influences the perfusion level of blood supplied via ECMO. This study aimed to investigate the impact of various cannula designs (side hole number) on intravascular flow patterns under different blood perfusion conditions. Six return cannula models with different side hole number and three cardiac output waveforms were designed based on clinical data for comparative analysis. The position of the blood mixing zone (MZ) was influenced by the flow-volume ratio of the heart output (CO/(CO+Qec)) and cannula design. As the CO/(CO+Qec) and the number of side holes in the cannula increased, the MZ shifted from the ascending aorta to the descending aorta. Concurrently, aortic wall and scalar shear stress on the impact side of ECMO cannulation reduced progressively. Return cannula with side holes effectively mitigated discrepancies in the perfusion of the renal artery and inadequate perfusion of the lower limb vessels on the cannula side while simultaneously reducing damage to the vessel walls and blood. However, increasing the number of side holes in the return cannulas resulted in diminished perfusion of the aortic arch bifurcation vessels by hyperoxic blood supplied via ECMO. Increasing the number of return cannula side holes for VA ECMO femoral artery cannulation improves hypoxic perfusion in the lower limb and reduces vascular endothelial injury, but may also lead to inadequate hypoxic perfusion in the upper body.