In this work, the pollutant reduction performance in landfill leachate by combining both photo-Fenton and biological processes was investigated. First, conventional biological treatment was performed, consisting of a decantation process, with centrifugation at 5000 rpm for 15 min, followed by the biological process conducted at 2.36 ± 0.1 mg mg −1 (BOD 5 /MLSS) and 0.571 ± 0.04 vvm (L L −1 min −1 ) for 40 h. At the same time, in the application of the photo-Fenton process, a central composite rotatable design (CCRD) was applied to evaluate the effect of main process variables. The quadratic models of chemical oxygen demand (COD) and 5 days biological oxygen demand (BOD 5 ) removal were proposed and validated, being separately used as objective functions during the search for optimal operating conditions. After the application of the conventional biological process, removals of 87 ± 2% and 84 ± 2% were obtained for COD and BOD 5 , respectively. For the photo-Fenton process under optimum conditions (3400 mg H 2 O 2 L −1 , 80 mg Fe 2+ L −1 , pH = 2.40 and 120 min), removals of 89 ± 3% COD and 75 ± 1% BOD 5 were obtained. However, both processes did not meet effluent discharge standards. So, the optimized photo-Fenton process was then combined with the biological process, performed for 150 h with 1.571 ± 0.06 vvm and 4.41 ± 0.3 mg mg −1 (BOD 5 /MLSS). With the combined process, it was possible to treat an effluent with high organic load, achieving a removal of 98% COD and BOD 5 and meeting the restrictive standards of release in recipient water bodies.