In this paper, the response surface methodology (RSM) was proposed for studying the synergistic extraction of chromium(III) ions by double-carrier supported liquid membrane (DCSLM) with organophosphorus carriers (D2EHPA/Cyanex272). At first, the optimization method of “one-factor-at-a-time” was adopted for determination of the best conditions for Cr(III) extraction by SLM with only one carrier (D2EHPA). The optimum/threshold D2EHPA concentration in the membrane phase increased linearly with initial concentration of Cr(III) ions in the feed phase. After the addition the second carrier (Cyanex272), the synergistic effect was observed. The largest percentage of extraction and the shorter time was obtained. The optimization of the synergistic extraction in DCSLM system by RSM using Box–Behnken design (BBD) for three variables (concentration and proportions of the carriers, initial concentration of Cr(III), and time of the process) was studied. The statistical model was verified with the analysis of variance (ANOVA) for the response surface quadratic model. The reduced quadratic model showed that the predicted values were in agreement with those obtained experimentally, as well as the fact that the concentrations and proportions of the carriers had a significant influence on the response. The developed model was considered to be verified and can be used to predict the optimal condition for the chromium ions extraction.