Flexible electronics have attracted great interest because of their potential applications in healthcare monitoring and human-computer interaction. The performance of flexible electronics depends on the design of structure, materials, and mechanical responses. In this work, we explore the use of polyurethane (PU) sponge as the scaffold to form flexible piezoresistive pressure sensors with conductive networks made from conductive polymer PEDOT:PSS and MXene nanosheets. The sensitivity of the prepared pressure sensors reaches 0.2171 kPa−1 under mechanical pressure in a range of 1.8–6.15 kPa. The prepared pressure sensors are re-usable after washing. The applications of the prepared pressure sensors in the sensing of physiological behavior are demonstrated under the action of finger tapping, finger bending, vocal cord vibration, swallowing, and pulsing of radial artery. The prepared pressure sensors have great prospects for applications in human-machine interaction and physiological diagnosis.