In this study, the Box-Benkhen design and response surface method (RSM) were applied to evaluate and optimize the operating variables during the treatment of tetrahydrofuran (THF) wastewater by Fenton process. The four factors investigated were initial pH, Fe2+ dosage, H2O2 dosage and reaction time. Statistical analysis showed the linear coefficients of the four factors and the interactive coefficients such as initial pH/Fe2+ dosage, initial pH/H2O2 dosage and Fe2+ dosage/H2O2 dosage all significantly affected the removal efficiency. The RSM optimization results demonstrated that the chemical oxygen demand (COD) removal efficiency could reach up to 47.8% when initial pH was 4.49, Fe2+ dosage was 2.52 mM, H2O2 dosage was 20 mM and reaction time was 110.3 min. Simultaneously, the biodegradability increased obviously after the treatment. The main intermediates of 2-hydroxytetrahydrofuran, γ-butyrolactone and 4-hydroxybutanoate were separated and identified and then a simple degradation pathway of THF was proposed. This work indicated that the Fenton process was an efficient and feasible pre-treatment method for THF wastewater.