Electrochemical oxidation combined with reagents of O3, H2O2 and FeCl2 was conducted in this study to treat the wastewater from wet fermentation of Yunnan arabica coffee. In addition, the effect of oxidants on the efficiency of wastewater treatment, the binding capacities of the oxidants to proteins, the degradation of organic pollutants in the wastewater, and the formation of oxidized organic components were systematically investigated. The results reveal better performance of O3-combined electrochemical oxidation (63.60% COD removal efficiency) for treatment of organic species in coffee wastewater than that of the electrochemical processes with H2O2 (47.70% COD removal efficiency) and FeCl2 (34.48% COD removal efficiency). The synergy of the electrooxidation/O3 process (0.0133 A/cm2, 20 mg/L–2 L/min) could not only raise the pH value (3.70~4.20, 5.14~5.44) of the wastewater and reduce the NaOH dosage of 2.80~3.7 g/L, but also effectively degrade the proteins, lipids, unsaturated hydrocarbons, and carbohydrates, with a total chemical oxygen demand (COD) value above 20,000 mg/L. After the oxidation treatment, some organic components remained in the wastewater, including 31.94% of S-containing organics, lignin, condensed aromatic compounds, and aromatic structural compounds, which are difficult to be utilized by microorganisms. In addition, it was found that OH− could bind to proteins and affect the required amount of NaOH addition, whereas the protein binding energy of O3 is higher than that of H2O2, indicating a stronger ability of O3 to oxidize proteins. Therefore, the combination of O3 and electrochemical oxidation can be considered as an effective method to treat organic pollutants in the wastewater from wet fermentation of Yunnan arabica coffee.