This work assessed the treatment of ketoprofen (KTP) using persulfate (PS) based Advanced Oxidation Process (AOP) activated thermally, chemically (Fe2+) or by UV. KTP degradation was optimized by manipulating several experimental parameters to achieve efficient KTP and its byproducts removal. Parameters included: PS concentration, Fe2+ concentration, temperature, pH, dissolved ions e.g. Cl-, HCO3-, and humic acids (HA). Results showed that: (i) KTP degraded significantly in UV only systems in contrary to thermal and chemical systems where KTP was resistant in PS free solutions; (ii) KTP degradation extent increased with the increase in [PS](0) while it was highly dependent on the [Fe2+](0):[PS](0) molar ratio; (iii) The activation energy (E-A) calculated in thermal activation experiments was found to be 157.02 (+/- 8.9) kJ mol(-1); (iv) The highest % reaction stoichiometric efficiency calculated only in thermal systems reached 38%; (v) Sequential KTP additions showed that the UV system was the most sustainable, followed by the thermal system while the chemical system was the least sustainable. (vi) KTP dissolved in a non-treated waste water matrix was best removed along with present coli-forms in UV system. KTP transformation products were identified by HPLC/MS and a degradation reaction pathway was suggested. This study led to the conclusion that UV/PS systems are the most economically efficient among the three investigated PS-based systems.