In this study, a flexible piezoelectric sensor based on polyacrylonitrile (PAN), zirconium-based MOF (UiO-66) with nitro (NO2) and two-dimensional material MXene composite nanofiber film was proposed. When pressure was applied, the three-dimensional structural nanopores were compressed, increasing the intercalation structure between the MXene nanosheets coated in the fibers. The double-packed system produced a higher resistance change under the same pressure load, which can be explained by the fact that the low-conductivity octahedral UiO-66-NO2 particles acted as a similar “buffer” between the highly conductive MXene. At the same time, a large number of hydrogen bonds between the surfaces of the two fillers enhanced the synergistic effect and promoted the interfacial coupling effect, so that more 31-helical conformation in the PAN matrix was converted into a planar zigzag conformation. This improved the piezoelectric performance and enabled the sensor to have a voltage output of about 200 V in the detection range. And because the polyhedral form of UiO-66-NO2 particles provided a rougher surface structure, the piezoelectric sensor can achieve a high sensitivity of 5.62 V/N. The other results showed that the dielectric constant of the designed flexible piezoelectric sensor was increased to 2.67, the dielectric loss was kept at a low level of 0.026, and the maximum elongation was 56.03 %. This multifunctional sensor shows great potential in the fields of health and medical treatment, human-computer interaction, etc.