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[Display omitted] • Sonolytic degradation of the model antibiotics (ABX) in water is faster than in milk. • ABX with high hydrophobicity favours their sonolysis in water and milk. • ABX are mainly oxidized by •OH, and additive H 2 O 2 enhances the sonolysis. • No obvious change in nutrients in milk were observed after sonication. • No antimicrobial activity in milk were determined after sonication. Antibiotics (ABX) residues frequently occurred in water and cow milk. This work aims to understand the kinetics and mechanisms of sonolytic degradation of four ABX, i.e. ceftiofur hydrochloride (CEF), sulfamonomethoxine sodium (SMM), marbofloxacin (MAR), and oxytetracycline (OTC) in water and milk. In both water and milk, the sonolytic degradation of ABX follows pseudo-first order (PFO) kinetics well (R 2: 0.951–0.999), with significantly faster ABX degradation in water (PFO kinetics constants (k 1): 1.5 × 10−3-1.2 × 10−1 min−1) than in milk (k 1 : 3.5 × 10−4-5.6 × 10−2 min−1). The k 1 values for SMM degradation in water increased by 118% with ultrasonic frequency (40–120 kHz), 174% with ultrasonic frequency (80–500 kHz), 649% with ultrasonic power (73–259 W), 22% with bulk temperature (12–40℃), and by 68% with reaction volume (50–250 mL), respectively, in other things being equal. The relevant k 1 values in milk increased by 326%, 231%, 122%, 10% as well as 82% with the above same effective factors, respectively. The oxidation by free radicals generated in situ dominates ABX degradation, and the hydrophobic CEF (54.0–971.7 nM min−1) and SMM (39.2–798.4 nM min−1) underwent faster degradation than the hydrophilic MAR (33.9–751.9 nM min−1) and OTC (33.8–545.3 nM min−1) in both water and milk. Adding an extra 0.5 mM H 2 O 2 accelerated SMM degradation by 19% in water and 33% in milk. After 130–150 min sonication of 100 mL of 2.0 mg L−1 (6.62 μ M) SMM in various milk with 500 kHz and 259 W, the residue concentrations (52.9–96.3 μ g L−1) can meet the relevant maximum residue limit (100 μ g L−1). [ABSTRACT FROM AUTHOR]