Polypyrrole (PPy) is a good candidate material for piezoresistive pressure sensors owing to its excellent electrical conductivity and good biocompatibility. However, it remains challenging to fabricate PPy-based flexible piezoresistive pressure sensors with high sensitivity because of the intrinsic rigidity and brittleness of the film composed of dense PPy particles. Here, a rational structure, that is, 3D-conductive and elastic topological film composed of coaxial nanofiber networks, is reported to dramatically improve the sensitivity of flexible PPy-based sensors. The film is prepared through surface modification of electrospun polyvinylidene fluoride (PVDF) nanofibers by polydopamine (PDA), in order to homogeneously deposit PPy particles on the nanofiber networks with strong interfacial adhesion (PVDF/PDA/PPy, PPP). This unique structure has a high surface area and abundant contact sites, leading to superb sensitivity against a subtle pressure. The as-developed piezoresistive pressure sensor delivers a low limit of detection (0.9 Pa), high sensitivity (139.9 kPa(-1)), fast response (22 ms), good cycling stability (over 10,000 cycles), and reliability, thereby showing a promising value for applications in the fields of health monitoring and artificial intelligence.