Chlortetracycline (CTC), which has been frequently detected in surface water, is generated primarily by the discharge of high-concentration CTC wastewater from pharmaceutical and livestock plants. The development of effective CTC degradation technology is critical. In this study, the extent of CTC degradation at 80 mg/L was investigated by combining hydrodynamic cavitation (HC) and hydrogen peroxide (H₂O₂). The results indicate degradation ratios of 88.7% and 93.8% at 5 and 30 min, respectively. Furthermore, the possible mechanisms of CTC degradation were determined via HPLC-MS. The CTC degradation pathways include ring openings, C–N bond cleavage, demethylation, dehydroxylation, and desaturation in the sole system of HC, and a series of additional reactions, such as glycine conjugation and the cleavage of C–C double bonds, occurs in the binary system of HC + H₂O₂. Nevertheless, the treated water poses ecological risks and cannot be directly discharged into the environment. Therefore, HC + H₂O₂ treatment may be a rapid and effective primary method for the degradation of high-concentration CTC in pharmaceutical factories.