The objective of this study is to quantify the detailed three-dimensional (3D) pulsatile hemodynamics, mechanical loading, and perfusion characteristics of a patient-specific neonatal aortic arch during cardiopulmonary bypass (CPB). The 3D cardiac magnetic resonance imaging (MRI) reconstruction of a pediatric patient with a normal aortic arch is modified based on clinical literature to represent the neonatal morphology and flow conditions. The anatomical dimensions are verified from several literature sources. The CPB is created virtually in the computer by clamping the ascending aorta and inserting the computer-aided design model of the 10 Fr tapered generic cannula. Pulsatile (130 bpm) 3D blood flow velocities and pressures are computed using the commercial computational fluid dynamics (CFD) software. Second order accurate CFD settings are validated against particle image velocimetry experiments in an earlier study with a complex cardiovascular unsteady benchmark. CFD results in this manuscript are further compared with the in vivo physiological CPB pressure waveforms and demonstrated excellent agreement. Cannula inlet flow waveforms are measured from in vivo PC-MRI and 3 kg piglet neonatal animal model physiological experiments, distributed equally between the head-neck vessels and the descending aorta. Neonatal 3D aortic hemodynamics is also compared with that of the pediatric and fetal aortic stages. Detailed 3D flow fields, blood damage, wall shear stress (WSS), pressure drop, perfusion, and hemodynamic parameters describing the pulsatile energetics are calculated for both the physiological neonatal aorta and for the CPB aorta assembly. The primary flow structure is the high-speed canulla jet flow ( at peak flow), which eventually stagnates at the anterior aortic arch wall and low velocity flow in the cross-clamp pouch. These structures contributed to the reduced flow pulsatility (85%), increased WSS (50%), power loss (28%), and blood damage (288%), compared with normal neonatal aortic physiology. These drastic hemodynamic differences and associated intense biophysical loading of the pathological CPB configuration necessitate urgent bioengineering improvements—in hardware design, perfusion flow waveform, and configuration. This study serves to document the baseline condition, while the methodology presented can be utilized in preliminary CPB cannula design and in optimization studies reducing animal experiments. Coupled to a lumped-parameter model the 3D hemodynamic characteristics will aid the surgical decision making process of the perfusion strategies in complex congenital heart surgeries.