Separation of samarium and lutetium was investigated through solvent extraction from their mixed aqueous species using commercial extractants of D2EHPA and PC88A. The Response Surface Method (RSM) was utilized to design the solvent extraction experiments. In which, a Central Composite Design (CCD) was applied to set the optimum conditions for highest separation factors between Sm and Lu. Design of Experiments (DOE) was conducted by making use of four operating variables, namely initial pH of the aqueous solutions (A: 0.2–2.6), extractant concentration (B: 0.01-0.09 molar), mole fraction of D2EHPA in the extractant mixture (C: 0 - 0.8) and a type of acidic solution (D: sulfuric and nitric acid) at three levels. The results indicated that the initial pH was the most paramount variable in solvent extraction of samarium and lutetium, while in the case of lutetium, the molar fraction of D2EHPA in the mixed extractants was non-influential. The statistical model predictions were confirmed by experiments for both samarium and lutetium extraction with high validity parameter of 97 and 98%, respectively. The optimum conditions for samarium and lutetium separation were identified as: A=0.8, B= 0.05, C= 0.2 and D= sulfuric acid. According to the findings of the model, the desirability value at the optimum conditions was evaluated as about 0.93, in which 71% of lutetium was extracted while the amount of extracted samarium was only less than 1%.