Froth flotation is widely used for concentration of base metal sulphide minerals in complex ores. One of the major challenges faced by flotation of these ores is selection of the type of flotation reagents. In this study, the D-optimal experimental design method was applied to determine the optimum conditions for flotation of copper and molybdenum in the rougher flotation circuit of the Sungun copper concentrator plant. The investigated parameters included types and dosages of collectors and frothers, diesel dosage and feed size distribution. The main effects on copper and molybdenum recoveries and grades were evaluated. Results of optimization showed that the highest possible grade and recovery were obtained for Z11 as a primary collector (20 g/Mg), R407 as a first promoter collector (20 g/Mg), X231 as a second promoter collector (7 g/Mg), A65 (15 g/Mg) and Pine oil as frothers (5 g/Mg), 20 g/Mg of diesel dosage, and d80 of feed size was equal to 80 μm. The analysis of variance showed that the primary promoter collector was the most significant parameter affecting the recovery of Cu, while diesel dosage and d80 were the most significant parameters influencing the Mo recovery.