Background: A vascular closure device (VCD) may be employed to close arteriotomy of the femoral artery following endovascular surgery, catheterization, and extracorporeal life support cannulation. Such devices aim to reduce the time to hemostasis and avoid the need for manual compression. Despite ubiquity of VCDs in clinical practice, limited research on the hemodynamic impact of these devices has been published. Methodology: Four commonly-used VCDs were applied on a 10 mm longitudinal incision in a 3/8 inch diameter polyvinylchloride tubing for geometry. Each sample was imaged with micro-computed tomography and reconstructed into a 3-dimensional model. Using computational fluid dynamics, blood flow over the 4 VCDs was simulated in a straight cylinder. In addition, 1 sample was simulated in a patient-specific femoral artery geometry. Time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and endothelial cell activation potential were used to assess the impact of each device on vessel hemodynamics. Results and Conclusions: The results suggest that anchor-based devices, resulted in larger flow disturbances, decreasing TAWSS and increasing OSI in their wake, compared with suture-based devices. Such conditions are likely to be pro-thrombotic. While the choice of VCD may be multifactorial, the present study offers new comparative data on their hemodynamic impact. Clinical Impact: The results from the present study offer unique comparative data on the hemodynamic impact of 4 vascular closure devices. These findings may help in the selection of devices. The pro-thrombotic nature of anchor-based devices may make these less suitable for certain clinical scenarios where there is a high risk of thrombosis and vessel occlusion.