Although different kinds of microengineering have been developed in piezoresistive fibers recently, it is still challenging to achieve a high-pressure sensitivity in these fibers. This is because these microstructures can only geometrically increase the conducting paths under pressure. In this work, via the theoretical calculation and practical experiments, we firstly demonstrated that not only the conducting paths but also the fibers’ elastic moduli of compression exhibit key roles in improving the sensitivities in fibers. Typically, by adjusting the kinetic diffusion coefficient between the spinning dope and the coagulation solution in wet-spinning, various structured (solid, hollow, porous, and hollow-porous) thermoplastic polyurethane (TPU) fibers with variable elastic moduli of compression were developed in this work. As a result, the piezoresistive fiber with a uniform and through porous structure (porous in both the core and the surface) exhibited the highest sensitivity of 0.67 kPa−1 due to its synergic improvement in conducting paths and contact area (with a low elastic modulus of compression of 6.98 kPa) under pressure. To the best of our knowledge, it is the recorded highest sensitivity in the piezoresistive fibers. Beyond the pressure sensing, we also proved the as-prepared porous fibers with an ultra-high stretchability of 2110%, a high performance in strain sensing, and a good candidate in humidity and gas sensing. At last, we successfully applied the piezoresistive fibers in our daily life for wearable sensing, demonstrating its high potential in practical application.