The objective of this work was to optimize the synthetic dairy effluent (SDE) treatment using the central composite rotatable design (CCRD) and the Doehlert matrix to evaluate the adjustment of the models to the data, besides verifying if it is possible to find the same optimum point to the turbidity removal, chemical oxygen demand (COD), and UV254 compounds using two experimental designs. The coagulation and flocculation assays were made in jar test and the flotation in a flotatest in bench scale. For each experimental design, the effect of two organic coagulants was evaluated in the removal of turbidity, COD, and UV254 compounds of the SDE: the polyacrylamide (PAM) and the Tanfloc. The generated mathematical models in both experimental designs adjusted well to the data, showing a high capacity of prediction. To the PAM coagulant, the optimal point found in the CCRD design was 46.49 mg L−1 of coagulant in a pH of 6.53; in the Doehlert design, the optimal point in the CCRD was 48.40 mg L−1 of coagulant in a pH of 6.50. When Tanfloc was used, in the CCRD, the optimal point found was 40.42 mg L−1 of coagulant in a pH of 5.00 and, in Doehlert design, the optimum found was 37.57 mg L−1 in a pH of 5.05. It is concluded that, using a smaller number of runs, through Doehlert design is possible to find the optimal point really close to the obtained through CCRD in which are observed efficiencies of similar pollutant removal.