<p>Mariculture wastewater often contains emerging contaminants and elevated chloride concentrations, posing significant treatment challenges. This study developed and assessed a novel process that integrates hydrodynamic cavitation with calcium peroxide for the removal of the antibiotic tetracycline. The hydrodynamic cavitation/calcium peroxide system exhibited superior tetracycline degradation across a wider pH range compared to the homogeneous Fenton-like system, achieving over 92% removal at pH 3 with a synergistic coefficient of 9.40, while maintaining 61% efficiency under neutral conditions. Additionally, it achieved a chemical oxygen demand removal rate of 50.73% from actual mariculture wastewater, surpassing the performance of the homogeneous Fenton-like system. This approach also significantly reduced the formation of toxic disinfection by-products. The concentrations of trihalomethanes (0.29 µg/L), dichloroacetic acid (1.38 µg/L), and trichloroacetic acid (0.41 µg/L) were lower than those produced by the homogeneous Fenton-like system, resulting in an effluent with a markedly reduced toxicity-weighted concentration. Liquid chromatography-mass spectrometry analysis did not identify any stable large-molecule chlorine-containing intermediate products. Coupled with experiments on the hydrodynamic cavitation degradation of dichloroacetic acid, these findings suggest that the extreme conditions generated by hydrodynamic cavitation can effectively disrupt the C–Cl bond, thereby preventing the accumulation of chlorine-containing by-products. This study establishes the hydrodynamic cavitation/calcium peroxide system as an efficient and environmentally safe technology for the treatment of antibiotic-contaminated high-salinity wastewater.</p>