The three-dimensional (3D) flexible piezoresistive sensors have promising potentials in wearable electronics because of their abundant structure forms and sensing functions. It is desired to develop 3D flexible piezoresistive sensors with high sensitivity and good stability. Herein, highly sensitive, stable and 3D flexible piezoresistive sensor with novel surface-filled (SF) graphene nanosheets (GNs) conductive layer was fabricated by fused deposition molding (FDM) 3D printing. Due to the surface-filled GNs conductive layer, the flexible piezoresistive sensor shows high stretchability of 1960% strain, good sensitivity of 175.57 kPa−1 at an applied pressure <300 Pa, high gauge factors of 18.95 (0–50% strain) and 66.29 (50–100% strain), excellent stability (>2000 cycles), the short mechanical response time (105 ms) and recovery time (66 ms). Compared with the SF-CNTs@styrene-ethylene-butylene-styrene (SEBS) sensor, the sensitivity of the SF-GNs@SEBS sensor is increased by 15.6%, and the GF values are increased by 167% (0–50%) and 974% (50–100%) respectively, indicating that GNs is more suitable for the sensor with the SF structure than CNTs. After 2000 compression/release cycles, the response signal of the GNs surface-filled sensor is basically not degraded, while the response signal of the GNs surface-coated sensor is degraded by 50%, indicating that the GNs surface-filled sensor has a far better stability than the GNs surface-coated sensor. Besides, the piezoresistive sensor was demonstrated the applications in detecting human activities, such as speaking, finger tapping, cheek bulging, and neck bending, exhibiting its great potential for application in health monitoring.