In this paper, the physico-chemical treatment of municipal wastewater for the simultaneous removal of pollutant indicators (chemical oxygen demand (COD) and total coliforms) and organic contaminants (total phenols) was investigated and assessed. A secondary settled effluent was subjected to coagulation, disinfection and absorption in a multifunctional reactor by dosing, simultaneously, aluminum polychloride (dose range: 0–150 μL/L), natural zeolites (dose range: 0–150 mg/L), sodium hypochlorite (dose range: 0–7.5 mg/L) and powder activated carbon (dose range: 0–30 mg/L). The treatment process was optimized using computational fluid dynamics (CFD) and response surface methodology. Specifically, a Latin square technique was employed to generate 16 combinations of treating agent types and concentrations which were pilot tested on an 8 m3/h multifunctional reactor fed by a secondary effluent with COD and total coliform concentrations ranging from ≈20 to 120 mg/L and from 105 to 106 CFU/100 mL, respectively. Results were promising, indicating that removal yields up to 71% in COD and 5.4 log in total coliforms were obtained using an optimal combination of aluminum polychloride (dose range ≈ 84–106 μL/L), powder activated carbon ≈ 5 mg/L, natural zeolite (dose range ≈ 34–70 mg/L) and sodium hypochlorite (dose range ≈ 3.4–5.6 mg/L), with all treating agents playing a statistically significant role in determining the overall treatment performance. Remarkably, the combined process was also able to remove ≈ 50% of total phenols, a micropollutant known to be recalcitrant to conventional wastewater treatments.