The cavitation inception threshold of mechanical heart valves has been shown to be highly variable. This is in part due to the random distribution of the initial and final conditions that characterize leaflet closure. While numerous hypotheses exist explaining the mechanisms of inception, no consistent scaling laws have been developed to describe this phenomenon due to the complex nature of these dynamic conditions. Thus in order to isolate and assess the impact of these varied conditions and mechanisms on inception, a system of ordinary differential equations is developed to describe each system component and solved numerically to predict the minimum pressure generated during valve closure. In addition, an experiment was conducted in a mock circulatory loop using an optically transparent size 29 bileaflet valve over a range of conditions to calibrate and validate this model under physiological conditions. High-speed video and high-response pressure measurements were obtained simultaneously to characterize the relationship between the valve motion, fluid motion, and negative pressure transients during closure. The simulation model was calibrated using data from a single closure cycle and then compared to other experimental flow conditions and to results found in the literature. The simulation showed good agreement with the closing dynamics and with the minimum pressure trends in the current experiment. Additionally, the simulation suggests that the variability observed experimentally (when using dP/dt alone as the primary measure of cavitation inception) is predictable. Overall, results from the current form of this lumped parameter model indicate that it is a good engineering assessment tool.