This work aimed to perform selective experimental arrays based on the electro-Fenton hybrid (EFH) process for pollutants abatement and toxicity reduction in brewery wastewater (BW). Fenton and electrocoagulation (EC) methods were assessed preliminarily, including the Fe2+ catalyst yield and H2O2 loss. Each method performance on reducing total organic carbon (TOC) was assessed using a 33 full factorial design (FFD). Firstly, Fe2+ species were produced in short time ranges with the electric current density at 50 A m−2 and electrical conductivity at 1200 μS cm−1, followed by EFH experiments with an initial addition of 9.0 g L−1 H2O2. In three levels, initial pH (2.5–3.5) values, Fe2+ production-dedicated time (5–15 min), and H2O2 renovating percentage (70–90%) were also evaluated, assessing TOC removal. Secondly, nine EFH kinetics, upon the addition of an initial 9.0 g L−1 H2O2 along with H2O2 addition at 82.5%, every 5 min, and three levels for pH (3.0–3.4) were carried out, beginning after three Fe2+ production-dedicated times (4–6 min). Thirdly, another 60 min kinetic experiment was proposed, with an initial 6 min EC process, followed by a 39 min EFH process, and finally, a 15 min EC process, assessing TOC removal and remaining toxicity. A significant improvement in TOC removal performance, about 90%, along with high toxicity reduction was attained after a refined EFH-based treatment. Therefore, keeping permanent EFH conditions with more suitable parameters provided a unique perspective for removing highly significant pollutants.