The catalysis effectiveness and influence factors of CoFe2O4 nanoparticles were investigated with peroxymonosulfate (PMS) as oxidant. Meanwhile, the degradation mechanism of levofloxacin (LVF) and the toxicity of its degradation products were analyzed. Efficient LVF degradation (95.4%) could be achieved within 30 min in CoFe2O4/PMS system with the optimum reaction conditions. The removal efficiency of LVF was decreased from 94.66% to 27.38% as the concentration of HCO3− increased from 0 to 20 mM, while increased to nearly 100% with 5 mM H2PO4− addition. The inhibition effect of Cl− on LVF removal decreased as the concentration of Cl− increased, and the addition of humic acid did not affect the final removal efficiency of LVF significantly. According to the results of degradation experiments and XPS analysis, both Co(II)/Co(III) and Fe(II)/Fe(III) redox pairs were involved in PMS catalysis, and Co(II)/Co(III) played a dominant role. SO4•− was the dominant free radical in CoFe2O4/PMS system for LVF degradation, and five possible degradation pathways were proposed based on the eleven degradation products. Compared with LVF, more toxic degradation products were generated in degradation pathways of decarboxylation and conversion of quinolone moieties, due to the coexisting of SO4•− and HO•. Meanwhile, the luminescence inhibition ratio of the reaction solution (23.5%) was still higher than the original LVF solution (21.4%) by the end of the experiment. Therefore, the degradation pathways that generate toxic products should be avoided or detoxification by the complete mineralization of LVF, which needs further research via the targeted optimization of CoFe2O4/PMS system.