Since conventional biological treatment methods are not sufficient alone to treat landfill leachate, this study investigated the efficacy of the heterogeneous Fenton process as a preliminary treatment technique. With this aim, a two-level factorial design combined with the response surface methodology (RSM) was used to optimize the operating parameters for the heterogeneous Fenton process used for treatment of leachate. The surface morphology and elemental analysis of Fe3O4 nanoparticles used in the heterogeneous Fenton process were completed with scanning electron microscope (SEM), energy dispersive X-ray (EDX) and Fourier transform infrared spectroscopy (FT-IR). In order to obtain maximum 75% chemical oxygen demand (COD) removal for treatment of leachate with the heterogeneous Fenton process, the optimum conditions for H2O2 and Fe3O4 dosages, stirring rate and initial pH parameters were 800 mg/L, 334.54 mg/L, 255 rpm and 3.34, respectively. The results obtained show the heterogeneous Fenton process abides by the second-order model (R2 = 0.9896), and the variables mentioned above were confirmed to significantly affect the COD removal efficiency. Response surface graphs show the use of higher pH and chemical agents do not increase the COD removal efficiency. This study proves the applicability of the multi-response optimization program for treatment of leachate from a landfill site representing a serious problem in environmental terms.