Self-calibration capabilities for flexible pressure sensors are greatly needed for fluid dynamic analysis, structure health monitoring and wearable sensing applications to compensate, in situ and in real time, for sensor drifts, nonlinearity effects, and hysteresis. Currently, very few self-calibrating pressure sensors can be found in the literature, let alone in flexible formats. This paper presents a flexible self-calibrating pressure sensor fabricated from a silicon-on-insulator wafer and bonded on a polyimide substrate. The sensor chip is made of four piezoresistors arranged in a Wheatstone bridge configuration on a pressure-sensitive membrane, integrated with a gold thin film-based reference cavity heater, and two thermistors. With a liquid-to-vapor thermopneumatic actuation system, the sensor can create precise in-cavity pressure for self-calibration. Compared with the previous work related to the single-phase air-only counterpart, testing of this two-phase sensor demonstrated that adding the water liquid-to-vapor phase change can improve the effective range of self-calibration from 3 psi to 9.5 psi without increasing the power consumption of the cavity micro-heater. The calibration time can be further improved to a few seconds with a pulsed heating power.