A diafiltration-nanofiltration-reverse osmosis (DiaNF-RO) process is introduced to achieve solutes fractionation of divalent/monovalent ions, i.e., Mg/Na, to enable resource recovery in seawater desalination and brine management. The diafiltration process is applied at the NF stage (i.e., DiaNF) to enhance the Mg/Na fractionation performance of NF (i.e., SF1Mg-Na), while the RO is incorporated to produce desalinated water as well as diluent required by the DiaNF. By initiating the ion fractionation at the pre-treatment rather than post-treatment (i.e., RO-NF), the DiaNF-RO mitigates challenges of high concentration in RO brine management, which includes limitation of maximum allowable operating pressure and high energy requirement. The semi-empirical model, with at least 77.4 % accuracy, is first applied to simulate the performance of DiaNF-RO at different operating conditions and configurations (i.e., multi-stage and recycling). The sensitivity analysis then suggests that dilution should only occur in the last NF stage and without any retentate recycling, while NF pressure and element number should be optimized. Using NF membrane with SFMg-Na of 1.28 at 10 bar and feed seawater of 35 g/L TDS, the optimal 4-stage DiaNF-RO design achieves maximum SF1Mg-Na of 12.19 at 5.72 kWh/m3, or a minimum energy consumption of 5.41 kWh/m3 at SF1Mg-Na of 7.04.