In recent years, wearable devices have developed rapidly. With its excellent performance, flexible piezoresistive sensors are widely used in human health monitoring, motion monitoring, artificial intelligence and wearable electronic devices. In this paper, a wearable flexible multilayer piezoresistive sensor based on mulberry silk fabric is designed. During the preparation of the flexible piezoresistive sensor, polydopamine (PDA), silver nanoparticles (AgNPs), MXene and polypyrrole (PPy) were coated on the surface of the mulberry silk fabric layer-by-layer, and then five layers of conductive fabric were stacked together, using 3M tape, PDMS resin and flexible wire for encapsulating. A wearable flexible multilayer piezoresistive sensor based on mulberry silk fabric is obtained. After testing, several substances have been successfully loaded onto the surface of mulberry silk fabric, and the effect of coating fabric is ideal. Furthermore the sensor shows excellent performance such as sensitivity of 2.0510 under low strain, sensitivity of 1.1171 under high strain and cycle stability of 1000 times, which is superior to the previously reported sensor based on fabric, and has broad application prospects.