Antibiotics have received great attention because of their abuse and potential hazards to the human health and environment. In the current work, peroxymonosulfate (PMS) was added to a cerium oxide (CeO2)/ultrasonic (US) system for tetracycline (TC) degradation. CeO2 nanoparticles (NPs) were synthesized by a simple and cost-effective method using Stevia rebaudiana leaf extract and cerium nitrate as precursors. The as-synthesized CeO2 NPs were characterized by X-ray diffraction, field emission scanning electron microscopy, and Fourier-transform infrared spectroscopy analysis. The effects of catalyst dosage, PMS concentration, US power, initial antibiotic concentration, and pH on TC removal were investigated. The results confirmed the formation of CeO2 NPs with a fluorite structure, spherical shape, and average particle size of 29 nm. The removal efficiency of TC was 92.6% in the optimum oxidation conditions ([TC] = 15 mg/L, [PMS] = 50 mM, [CeO2] = 0.6 g/L, pH = 6, and US = 70 W) and followed the zero-order kinetics. Experiment scavenger demonstrated both sulfate and hydroxyl radicals (SO4•-, •OH) were responsible for degrading antibiotics. Biogenic CeO2 NPs and ultrasound waves-activated PMS is a promising technology for water pollution caused by contaminants such as pharmaceuticals.