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The Virtual Mock Loop (VML) is a mathematical model designed to simulate mechanism of the human cardiovascular system interacting with mechanical circulatory support devices. Here, we aimed to mimic the hemodynamic performance of Cleveland Clinic's self‐regulating continuous‐flow total artificial heart (CFTAH) via VML and evaluate the accuracy of the VML compared with an in vivo acute animal study. The VML reproduced 124 hemodynamic conditions from three acute in vivo experiments in calves. Systemic/pulmonary vascular resistances, pump rotational speed, pulsatility, and pulse rate were set for the VML from in vivo data. We compared outputs (pump flow, left and right pump pressure rises, and atrial pressure difference) between the two systems. The pump performance curves all fell in the designed range. There was a strong correlation between the VML and the in vivo study in the left pump flow (r2 = 0.84) and pressure rise (r2 = 0.80), and a moderate correlation in right pressure rise (r2 = 0.52) and atrial pressure difference (r2 = 0.59). Although there is room for improvement in simulating right‐sided pump performance of self‐regulating CFTAH, the VML acceptably simulated the hemodynamics observed in an in vivo study. These results indicate that pump flow and pressure rise can be estimated from vascular resistances and pump settings. [ABSTRACT FROM AUTHOR]