The increasing presence of pharmaceutical pollutants, such as acetaminophen, in water bodies poses a significant environmental challenge due to their persistence and potential toxicity. This study investigated the enhanced photodegradation of acetaminophen using ZnO-NiO nanofibers as superior photocatalysts. The nanofibers synthesized with varying NiO contents (designated as ZN0.5, ZN1, ZN1.5, and ZN2), were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), Raman, FTIR, Brunauer-Emmett-Teller (BET) analysis, and diffuse reflectance spectroscopy (DRS) to elucidate their structural, morphological, and optical properties. Thermogravimetric analysis (TGA) indicated that the nanofibers exhibit high thermal stability, with major weight loss attributed to the decomposition of the polymer matrix and residual organics. The BET analysis revealed that the specific surface area remains stable after increasing the NiO content up to a certain ratio. This stability correlates with the enhanced photocatalytic performance due to increased light absorption and improved charge separation. The diffuse reflectance spectra and Kubelka-Munk plots demonstrated a reduction in bandgap energy with higher NiO content, facilitating greater visible light absorption. Photocatalytic experiments under visible light irradiation, in the presence of peroxymonosulfate (PMS), showed that the ZN1.5 nanofibers achieved the highest acetaminophen degradation rate, i.e., 92%, within 3 h. Mechanistic studies, supported by radical trapping experiments, revealed that the improved photocatalytic efficiency is due to the synergistic effects of ZnO and NiO heterojunctions, which enhance charge separation and reactive oxygen species (ROS) generation. This research highlights the potential of ZnO-NiO nanofibers as effective photocatalysts for the degradation of pharmaceutical pollutants. The findings demonstrate that optimizing the composition and structure of nanofibers can significantly improve their environmental remediation capabilities, providing a promising solution for sustainable water treatment.