The study is about the degradation of a widely used pharmaceutical and personal care product-salicylic acid by sonocatalysis, and the experimental design of the reaction system. The first part of the study consists of sonication (572 kHz) in the presence of zero-valent iron (ZVI) with or without H2O2 to select and optimize the operational parameters as frequency, time, initial solute concentration, dose of reagents and pH. The second part consists of the use of response surface methodology and multiple regression to develop an experimental design modeland to assess the individual and interactive effects of pH, power (P-o), ZVI dose and H2O2. The results showed that the optimal conditions predicted by the model without defining any restrictions are: pH = 2.0, P-o = 120 W, ZVI = 24 mg L-1, which provide total salicyclic acid and 48% TOC decay. However, the prediction implies intensive consumption of energy and reagents, and must therefore be modified by restricting the value of TOC decay to a lower value and that of pH to a higher one. Cross-validation tests showed that the prediction accuracy of the model was considerably high with 5.0-9.4% deviation from the experimental data.