<p>The pressure comfort of passengers and crew in high-speed trains faces significant challenges under alternating open-tunnel conditions. To better understand the mechanism of pressure transmission and control interior pressure fluctuations in high-altitude regions, this study develops an interior pressure fluctuation model. By establishing the frameworks of the non-ideal gas state equation and the polytropic process equation, gas heat transfer and mass transfer were expressed through the first law of thermodynamics and the continuity equation. Simulation results, evaluated by root mean square error, coefficient of determination, peak-to-peak error, and pressure change rate, show that the proposed model closely aligns with measured signals in both overall trends and local details. Data from various train types and tunnel scenarios further demonstrate the model’s accuracy and practical applicability. This study provides a critical foundation for evaluating interior pressure comfort for high-speed trains in high-altitude regions.</p>