Ciprofloxacin (CIP), as a common antibiotic used in human clinical and livestock farming, is discharged into natural water bodies and its concentration has increased in the last years. Its stable chemical structure is difficult to remove by conventional techniques. Residual ciprofloxacin in the environment has become an emerging micropollutant that promotes the generation of resistance genes of bacteria and endangers ecosystem balance and human health. Removal of ciprofloxacin from water by the system of ultrasound/electric field/sodium persulfate (US/E/PS) was investigated. Firstly, CIP degradation affects by different oxidation methods, such as ultrasonic oxidation, electro-oxidation, and persulfate oxidation, and their four combined oxidation methods (ultrasound-activated persulfate oxidation, electro-activated persulfate oxidation, ultrasound-enhanced electro-oxidation, and ultrasound-enhanced electro-activated persulfate oxidation), on the target contaminants were compared. Secondly, the influences of parameters on the CIP degradation by an ultrasound-enhanced electro-activation-persulfate reaction system were investigated. Thirdly, the possible free radical species in the ultrasound-enhanced electro-activation-sulfate reaction system were identified and the dominant free radical species in the system were analyzed. Finally, the samples of CIP in the US/E/PS system were tested by liquid mass spectrometry, and the possible intermediate products and degradation path were speculated. The results indicate that the US/E/PS system is of great potential application value in the removal of organic pollution and environmental purification.