\In this study, ultrasound (US) technology was adopted for peroxymonosulfate (PMS) activation, and it increased the efficiency of sulfamethazine (SMT) antibiotic degradation. US can considerably activate PMS, increasing the SMT degradation rate by the US/ PMS process up to 6.4 and 86 times that of PMS alone and US alone processes, respectively. The scavenger quenching experiments and electron paramagnetic resonance (EPR) spectrometry proved that US can activate PMS to generate sulfate radicals (SO4-%) and hydroxyl radicals (% OH), which contributed to efficient SMT degradation in the US/ PMS system. Furthermore, density functional theory (DFT) calculations and dual descriptor were used to provide insights into SMT degradation. The calculation results offered good agreement with the experimental detection, which indicated that the central cleavages of SMT such as S-N, S-C, and N-C bonds or adducts on the rings would easily occur to degrade SMT in the US/ PMS system. Based on these results, SMT degradation pathways were deduced, and the overall performance of the US/ PMS process and its underlying mechanism for SMT degradation were proposed. This study offers theoretical and practical directions for removal of other antibiotics or pollutants using the US/ PMS process.