The enhancement of the ultrasound system by adding diverse oxidants to remove a model contaminant (acetaminophen, ACE) in water was investigated. Different parameters were evaluated to study their effect on both the degradation kinetics and the synergy of the combination. The variables studied were the ultrasonic frequency (575, 858, and 1135 kHz), type of oxidant (hydrogen peroxide, sodium peroxydisulfate (or persulfate, PDS), and potassium peroxymonosulfate (PMS)), ACE concentration (4, 8, and 40 µM), and oxidant concentration (0.01, 0.1, 1, and 5 mM). Particular interest was placed on synergistic effects, implying that one process (or both) is activated by the other to lead to greater efficiency. Interestingly, the parameters that led to the higher synergistic effects did not always lead to the most favorable degradation kinetics. An increase in ACE removal of 20% was obtained using the highest frequency studied (1135 kHz), PMS 0.1 mM, and the highest concentration of ACE (40 µM). The intensification of degradation was mainly due to the ability of ultrasound to activate oxidants and produce extra hydroxyl radicals (HO•) or sulfate radicals (SO4•-). Under these conditions, treatment of ACE spiked into seawater, hospital wastewater, and urine was performed. The hospital wastewater matrix inhibited ACE degradation slightly, while the urine components inhibited the pollutant degradation completely. The inhibition was mainly attributed to the competing organic matter in the effluents for the sono-generated radical species. On the contrary, the removal of ACE in seawater was significantly intensified due to "salting out" effects and the production of the strong oxidant HOCl from the reaction of chloride ions with PMS.