The efficacy of Fe2+-activated persulfate (PS) and hydrogen peroxide (HP) treatment in total organic load and selected organic pollutants removal from different highly polluted industrial effluents was evaluated and compared. The studied wastewater samples involved a paint production wastewater (S1), phenolic wastewater (S2) and mature landfill leachate (S3). The coagulation proved an effective technique to pre-treat S1, and thus to reduce substantially the amount of chemicals required in the subsequent oxidation step. The Fenton treatment (HP/Fe2+) proved more effective S1 post-treatment technology than the PS/Fe2+ process and resulted in substantial COD and DOC removal as well as in considerable the BOD7/COD ratio increase. In the case of S2 and S3, the application of Fenton process also demonstrated higher total organic load removal efficacy than the PS/Fe2+ system. Conversely, the HP/Fe2+ oxidation was characterized by a temperature increase and excessive foam formation. The findings of this study provide valuable information for further full-scale applications of Fe2+-activated HP and PS based processes for the treatment of highly contaminated wastewater with the most effective concentrations of reagents used.