The specific objectives of this study were to optimize the TC degradation in aqueous solution using US/S2O82− process. Response surface methodology (RSM) is a reliable statistical technique for developing, improving and optimizing processes and can be used to assess the relative significance of several affecting factors with the least experiments [52–54]. Therefore, an experimental design methodology using RSM and CCD was used to evaluate the effect of operational parameters such as initial TC concentration, initial S2O82− concentration, initial pH and reaction time on the sonochemical degradation of tetracycline. In addition, the effect of temperature, degradation kinetics, mineralization, changes of ultraviolet Visible (UV–Vis) spectra and the proposed degradation pathway of TC by the US/S2O82− process were investigated. This study as part of a PhD dissertation of the first author was performed at Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences in 2015.