This study is focused on advanced oxidation technologies (AOTs) using the combined effect of Fe(0–VI)/sulfite systems, that produce mainly SO₄^•− radicals, to remove different 4-aminobenzene sulfonamides (SAs), namely sulfamethazine, sulfadiazine, sulfamethizole, from aqueous solutions. Results obtained showed that neither sulfite nor iron alone is able to degrade SAs; however, the combined effect depends on the oxidation state of iron species whose effectiveness to activate sulfite to promote the degradation of SAs increased following this order: Fe(III) < Fe(II) < Fe(0) < Fe(VI). Using Fe(VI)/sulfite, the complete removal of SAs was obtained in 5 min largely surpassing the effectiveness of the other three systems. The sulfonamides’ removal percentage was markedly influenced by sulfite concentration and dissolved oxygen, which improved the generation of oxidant radicals. Response surface methodology was applied, and a quadratic polynomial model was obtained, which allowed us to determine the percentage of SAs degradation as a function of both the iron species and sulfite concentrations. The study of the influence of the water matrix on these AOTs revealed an inhibition of SAs’ removal percentage when using ground water. This is probably due to the presence of different anions, such as HCO₃⁻, Cl⁻, and SO₄²⁻ in relatively high concentrations. According to the byproducts identified, the proposed degradation pathways include hydroxylation, SO₂ extrusion, and different bond-cleavage processes. Cytotoxicity of degradation byproducts, using MTS assay with HEK 293 and J774 cell lines for the first time, did not show an inhibition in cell proliferation, sustaining the safety of the process.