Abstract Penicillin G is an active pharmaceutical ingredient of great importance in health sectors. Meanwhile, because of its huge quantity production and resistance to biodegradability, this antibiotic is ubiquitously presented in aquatic environment. In this study, the degradation of effluent wastewater from Penicillin G production plant by Photo- Fenton process and Ultrasound process (Sonolysis) was investigated, the effects of different process variables in both methods were evaluated and at last the degradation of Pen-G by these two processes in the optimum conditions was compared. Pen-G concentration and Chemical Oxygen Demand (COD) were selected as the environmental parameters to follow the performance of Photo-Fenton process and Sonolysis. Optimum condition of Photo-Fenton process is in H2O2/Fe2+ molar ratio 20 (20 mM H2O2 and 1 mM Fe2+) and pH 3.5 and for Sonolysis (35 KHz) is in pH 3. Complete degradation of Pen-G occurred in 30 and 70 min for Photo-Fenton process and Sonolysis, respectively. Based on the results, Photo-Fenton process is more efficient in terms of both COD degradation and Pen-G removal than Sonolysis (35 KHz).