Background: Modern human patient simulators (HPSs) could be used for researching critical scenarios such as apnea oxygenation. We aimed to study the use of a high-fidelity HPS to assess prolonged apnea using various oxygenation strategies with a simple high-flow nasal cannula (15 L/min). Methods: An experimental simulation study using an HPS (CAE Healthcare™) was conducted after obtaining approval from the Institutional Review Board. The HPS responded according to real-time physiologically modeled responses to external gases, such as oxygen (O2). Apnea experiments were performed with different physiological settings, such as shunt fraction (5%) and O2 consumption (250, 500, and 750 ml/min). The following four apnea experiments were conducted: no oxygenation (NO), apnea oxygenation alone (AO), preoxygenation alone (PO), and para-oxygenation (PAO). The time to 92%, 75%, and 50% saturation was recorded. Alveolar and arterial gas levels were recorded till 50% saturation. Results: At 250 ml/min, PO (1121 s) and PAO (1274.5 s) had a significantly longer time to 50% saturation (400% increase) compared to NO (222.5 s) and AO (239 s). A similar trend was observed for the time to 92% and 75% saturation. At higher O2 consumption rates, a shorter time to desaturation was observed. Conclusions Apnea trends in the HPS correlated with similar prior human experiments. AO without preoxygenation was found to provide no additional benefit. Preoxygenation with high-flow O2 via nasal cannula prolonged the time to desaturation in the PAO more than PO scenario. Therefore, HPSs can be used in future studies where patient safety is a concern.