The photocatalysis-Fenton process was considered as an effective water treatment method due to its superior efficiency and technical feasibility, but its application was limited by ≡Fe(III)/≡Fe(II). Herein, Fe doped BiOCl hierarchical microspheres with rich surface oxygen vacancies (Fe/BiOCl OVs) were synthesized to modulate the interface structure for efficient photocatalysis-Fenton degradation of levofloxacin (LEV). The systematic characterization analysis confirmed the existence of strong interfacial interactions, which facilitated the activation of H2O2 and the degradation of LEV. The synergism of metal deposition, OVs and surface plasmon resonance (SPR) effect of Bi contributed to the enhanced light absorption ability and suppressed carriers recombination. The LEV degradation efficiency reached 99.0% after 60-min photocatalysis-Fenton reaction. The interfacial charge transfer theory demonstrated that the presence of oxygen vacancies accelerated the redox cycle of ≡Fe(III)/≡Fe(II), which promoted the H2O2 activation to produce ·OH. The ·OH and e- played important roles during the photocatalysis-Fenton degradation of LEV, while ·O2–, 1O2 and h+ also contributed in LEV degradation. Based on density-functional theory (DFT) calculations and LC-MS analysis, four degradation pathways of LEV were proposed. The photocatalysis-Fenton degradation process of Fe/BiOCl OVs effectively reduced the toxicity of LEV, which ultimately mitigated the harmful effects of antibiotics on the environment.