<p>Donnan Dialysis (DD) is a promising membrane-based technique for water softening that selectively removes divalent cations such as calcium and magnesium by exploiting electrochemical gradients across cation-exchange membranes. This study investigates the removal efficiency of calcium and magnesium from water using three Fujifilm cation-exchange membranes (Type 1, Type 2, and Type 10). Preliminary tests were carried out to assess the impact of critical factors, including the Na⁺ concentration in the receiver compartment and the concentrations of Ca²⁺ and Mg²⁺ in the feed compartment. Among the membranes tested, the Type 1 Fujifilm membrane exhibited the highest permeability, resulting in superior ion removal for both calcium and magnesium. The full factorial design analysis determined that the concentrations of calcium and magnesium in the feed compartment are the main factors affecting ion removal. Through the application of Response Surface Methodology (RSM), the interactions between these factors were uncovered, which are essential for optimizing complex processes like Donnan Dialysis. In addition, the technique is able to remove additional tests by predicting the best conditions for subsequent developments to come. In this case, the membrane of the Fujifilm Type 1 was able to remove ions with 93.78% efficiency at [Ca²⁺] = 120 mg/L, [Mg²⁺] = 80 mg/L, [Na⁺] = 0.55 mol/L (12,644.5mg/L). This study demonstrates that Donnan dialysis combined with RSM is a superior and environmental friendly water softening method. It is also promising in softening waters for industrial use because of its high ion removal efficiency.</p>