This work aims to study the degradation process using Sono-Fenton reactor for the treating of pharmaceutical wastewater loaded with cephalexin. The degradation process was tested as a function of pH (3-11), concentration of degradation agent H2O2 (40-80mg/L), metal catalyst agent Fe2+ (4-12mg/L), reaction time (up to 100min), and initial cephalexin concentration (50-100mg/L). The effects of these parameters were tested and optimized by using Box-Behnken response surface methodology (RSM). All the experiments were performed with exposure to ultrasonic irradiation of a frequency of 130kHz. According to the ANOVA results with a confidence level of 95%, a high regression and fitting values were obtained between the experimental degradation data of cephalexin and the RSM predicted model. This finding suggests that RSM is an extremely significant and accurate methodology to model the degradation process of cephalexin using Sono-Fenton reactor. Accordingly, the optimum degradation efficiency of 90% was obtained at conditions of pH 3, H2O2 concentration=60mg/L, Fe2+ concentration=8mg/L, cephalexin concentration=50mg/L, and reaction time=60min. Thus, the current study demonstrated that the Sono-Fenton reactor can be used effectively as an advanced oxidation treatment unit for degradation of cephalexin under optimized environmental conditions. [GRAPHICS] .