Despite increasing clinical interest in ambulatory extracorporeal membrane oxygenation (ECMO), its equipment is not optimally designed for portability. Blood pumps are too heavy for ambulation, as the lightest system on the market weighs more than 10 kg. Recently, the authors have published a series of preclinical sheep studies that used ventricular assist devices (VAD) as part of the Pulmonary Assist System to improve portability of an extracorporeal life support technology. Here, data from those prior publications were used to evaluate a semi-empirical model that predicts the pressure-flow relationship in a VAD-pumped extracorporeal circuit. Three types of VAD pumps were evaluated in a single-site VV ECMO circuit in these prior studies. The semi-empirical model had an 11% ± 26% error in predicting achievable blood flow. Using this model, different circuit configuration scenarios were simulated to determine the range of operable flow. The highest flow from simulations was 3.76 L/min with a 30-French dual-lumen cannula, VAD, and a clinical oxygenator. The most sensitive parameter affecting flow was the cannula size. For long-term use, the oxygenator’s thrombotic tendency would decrease the achievable flow over time. This semi-empirical model provides a simple framework to illustrate the relationship between circuit component selection, achievable blood flow, and oxygen transfer.