Fleroxacin (FLE) is an emerging third-generation fluoroquinolone antibacterial agent (FQs) that has been frequently detected in aqueous environments. However, there is a lack of sufficient knowledge regarding the transformation mechanisms of FLE within drinking water distribution systems (DWDSs) when residual chlorine and ClO2 are present. To address this gap, this study makes the first attempt to explore the kinetics, transformation byproducts and toxicity variations during fleroxacin (FLE, an emergent pollutant) degradation by chlorine and ClO2 in a pilot-scale DWDSs. The obtained results show that (i) the FLE degradation rate by chlorine was higher than by ClO2 at pH 7.4 in the pilot-scale DWDSs; (ii) the degradation efficiency of FLE was significantly affected by pH, with FLE degradation by chlorine possessing the highest rate at neutral pH, and the degradation rate was positively correlated with pH (from 6.5 to 9) during the ClO2 disinfection process; (iii) pipe materials can appreciably affect the relative performance of the FLE degradation efficiency by chlorine and ClO2; (iv) seven and eight intermediates are identified during chlorination and ClO2 oxidation, respectively, and the cleavage of the piperazine group was the committed step and the main oxidation reaction, and (v) the toxicity assessment demonstrates that the toxicity of FLE chlorination and ClO2 are both higher than the blank experiment, and ClO2 disinfection can reduce the potential risk compared to the chlorine disinfection.