The characteristic depressed hemodynamic state and gradually declining circulatory function in Fontan patients necessitates alternative postoperative management strategies incorporating a system level approach. In this study, the single-ventricle Fontan circulation is modeled by constructing a practical in vitro bench-top pulsatile pediatric flow loop which demonstrates the ability to simulate a wide range of clinical scenarios. The aim of this study is to illustrate the utility of a novel single-ventricle flow loop to study mechanical cardiac assist to Fontan circulation to aid postoperative management and clinical decision-making of single ventricle patients. Two different pediatric ventricular assist devices, Medos and Pediaflow Gen-0, are anastomosed in two nontraditional configurations: systemic venous booster (SVB) and pulmonary arterial booster (PAB). Optimum ventricle assist device strategy is analyzed under normal and pathological (pulmonary hypertension) conditions. Our findings indicate that the Medos ventricular assist device in SVB configuration provided the highest increase in pulmonary (46%) and systemic (90%) venous flow under normal conditions, whereas for the hypertensive condition, highest pulmonary (28%) and systemic (55%) venous flow augmentation were observed for the Pediaflow ventricular assist device inserted as a PAB. We conclude that mechanical cardiac assist in the Fontan circulation effectively results in flow augmentation and introduces various control modalities that can facilitate patient management. Assisted circulation therapies targeting single-ventricle circuits should consider disease state specific physiology and hemodynamics on the optimal configuration decisions.