The presence of antibiotics and their metabolites in natural waters has raised some concern among scientists around the world because it can lead to bacterial resistance and other unknown consequences to mankind and wildlife. Persulfate (PS)-driven oxidation is a new technology that has been used successfully to remediate contaminated sites, but its use to treat wastewater, especially sewage treatment plant (STP) effluent, is still scarce. This paper describes the effect of several persulfate activation methods for degrading sulfathiazole (STZ) in Milli-Q water and in STP effluent. Some parameters, such as pH, persulfate concentration, presence of Mn, Zn, Cu, Fe, and Fe, as well as copper and iron organic complexes, were studied in STZ degradation. Raising the pH from 5 to 9, as well as the persulfate concentration, resulted in increased STZ degradation. Among the transition metals evaluated, only Fe and Cu were able to activate persulfate molecules. Copper was a better activator than iron since its effect lasts longer. Citrate was the best ligand evaluated increasing Fe(II) activation capacity at pH 7. Hydroxylamine addition to Fe(II) on persulfate system extended the Fe(II) effect. The presence of bicarbonate or humic acid did not affect PS-driven degradation of STZ. Finally, the degradation of STZ in STP effluent promoted by PS-driven oxidation (25 °C) was as fast as in Milli-Q water, proving to be successful.