Veno-pulmonary extracorporeal membrane oxygenation (VP ECMO) is an emerging mechanical support therapy for patients with right ventricular (RV) injury. This study aimed to assess the hemodynamic impact of VP ECMO using a mock circulatory loop (MCL) to simulate patients with varying levels of RV injury and pulmonary vascular resistance (PVR). Right ventricular injury was simulated by changing the end-systolic pressure-volume relationship (47.5–100% of healthy RV), in combination with different PVR states (100–600 dyne·s·cm^–5). Veno-pulmonary extracorporeal membrane oxygenation was introduced into the MCL circuit from 0 to 5 L/min at 1 L/min intervals. We demonstrated that the effect of VP ECMO support on pulmonary and systemic hemodynamics may vary significantly depending on RV function and RV afterload. A common observation across all cases was that high ECMO flow rates increased mean pulmonary arterial and left atrial pressure and reduced pulmonary artery pulsatility significantly. The absolute value of these parameters depended highly on RV function and corresponding PVR state. The study highlights the importance of considering RV injury severity and corresponding afterload when using VP ECMO to maintain cardiorespiratory stability and prevent pulmonary vasculature damage or hemorrhage. Further research is needed to establish the safe and effective use of VP ECMO in managing cardiac or respiratory failure.