This work examined the oxidation of Piroxicam (PIR), a representative nonsteroidal anti-inflammatory drug using iron activated persulfate. The effect of persulfate dosing was vital for the efficiency of the process. The addition of 20 mg/L sodium persulfate (SPS) eliminated 500 μg/L of PIR in less than 20 min at natural pH. PIR decomposition followed pseudo-first-order kinetics, and the observed kinetic constant increased by 2.1 times when the initial concentration of PIR decreased from 2000 to 250 μg/L. Acidic pH favored the PIR destruction, while both sulfate and hydroxyl radicals are involved in PIR destruction at natural pH. The effect of inorganic ions like bicarbonate and chlorides was almost insignificant on PIR removal. The presence of humic acid reduced PIR removal from 100% to 67% after 20 min of treatment with 2 mg/L Fe2+ and 20 mg/L SPS. The experiment that was performed with bottled water showed similar efficiency with ultrapure water, while in the case of secondary effluent, PIR removal decreased by 26% after 30 min of treatment. The Fe2+/SPS/ultrasound hybrid process showed a low degree of synergy (18.3%). The ecotoxicity of aqueous solution using the Vibrio fischeri as an indicator was reduced during the treatment, although with a different trend from the removal of PIR, possibly due to byproducts derived from the oxidation of secondary effluent and PIR.