Portugal is the 11^th biggest wine producer in the world, with 6.4 MhL produced in 2020. This high production of wine leads to a great generation of a problematic agro-industrial effluent: winery wastewater (WW). WW presents elevated content of organic matter, polyphenols and low pH, therefore, it is necessary to treat the WW before it release into the environment. The aim of this work was (1) evaluate the application of the mixture potassium caseinate, bentonite and polyvinylpolypyrrolidone (PVPP) as a pre-treatment, (2) optimize the sulfate radical advanced oxidation process (SR-AOP) with a Box-Behnken design of Response Surface Methodology and (3) evaluate the combined treatment of coagulation-flocculation-decantation (CFD)-SR-AOP process. The Box-Behnken design was used to study the combinational effect of 3 influencing factors: sodium persulfate (SPS) concentration (15 – 75 mM), Fe²⁺ concentration (0.25 – 1.75 mM) and hydroxylamine (HA) concentration (0.00 – 8.75) on the total organic carbon (TOC) and chemical oxygen demand (COD) removal of a WW with a TOC and COD of 464 mg C/L and 1119 mg O₂/L, respectively. With the statistical model it was obtained the best operational conditions, as follows: [SPS] = 51.96 mM, [Fe²⁺] = 0,90 mM, pH = 3.0, radiation UV-A (365 nm), Temperature = 298 K, time = 300 min, with a TOC and COD removal of 19.7 and 31.2%, respectively. With the combination of CFD process ([potassium caseinate] = 0.4 g/L, [bentonite] = [PVPP] = 0.1 g/L, pH = 3.0, rapid mix (rpm/min) = 150/3, slow mix (rpm/min) = 20/20, sedimentation time = 12 h) and SR-AOP it was achieved 38.9 and 45.3% removal of TOC and COD, respectively. The combined treatment was applied to a WW with a higher TOC and COD (997 mg C/L and 4640 mg O₂/L) and it was achieved 51.2 and 73.3% removal, respectively. In conclusion the combined treatment reveals a good efficiency and potential to be applied in the treatment of agro-industrial wastewater.