Donnan dialysis is one of the membrane processes. It is based on the cross-exchange of ions having the same electric charge through an ion-exchange membrane. The removal of boron by Donnan dialysis was studied in this work. First, a preliminary study was conducted to determine the experimental field of operating parameters using two membranes (AFN and ACS). Then, a full factorial design was applied to investigate the influence of the operating parameters and their interactions on the boron removal. Response surface methodology using Doehlert design was adopted to predict the optimal conditions. This approach via experimental designs is more efficient than the conventional optimization approach (the “one-at-a-time” method) which is time-consuming and requires a large number of experiments.