Electro-Fenton (EF) is a system where electrooxidation and electrocoagulation come together. In the EF method, it is aimed at creating OH radicals in an electrochemical cell by catalyzing H2O2 with Fe2+ ions. In this study, optimization of process variables for the removal of reactive azo dye (reactive yellow 145) from aqueous solution by the electro-Fenton method was carried out using response surface methodology. The percentage of dye removal and energy consumption were selected as the response functions for the 5 variables determined as voltage, H2O2 concentration, pH, electrode spacing, and processing time. As a result of 32 experiments determined by the Design Expert 13 program, the effect of variables on response functions was examined separately and together. 10 V voltage to 99.4%, which is the highest removal; pH 2.5; 1 cm electrode range; 1 mL H2O2 addition; and 22.16 Wh/L energy consumption in a 70-min treatment time were reached. The optimum values of the variables proposed by the program to ensure the highest dye removal efficiency (approximately 93%) and the lowest energy consumption (approx. 3.4 Wh/L) are approximately 9.4 V voltage, pH 3.7, 2.5 cm electrode range, 1 mL H2O2 addition, and a 40-minute treatment time.