In this study, Internally Staged Design (ISD) was numerically optimized in order to demonstrate the long-term performance of full-scale seawater reverse osmosis (SWRO) membrane systems in the presence of colloidal foulants. To this end, a numerical model based on a finite difference method was developed and optimized with various feed water qualities, such as fouling potential and total dissolved solids (TDS). As a result, the optimized ISD exhibited greater water flux and higher energy efficiency in long-term operation (90 days) compared to conventional designs, where single-type membrane elements were employed over a pressure vessel while achieving potable TDS concentration in permeate (< 400 mg/L). This enhanced performance was attributed to the reduction of colloidal fouling on the lead elements and the alleviation of concentration polarization (CP) at the tail elements. Among fouling mechanisms, cake-enhanced concentration polarization (CECP) played a dominant role in flux decline at the lead elements, whereas CP was the chief flux decline mechanism at the tail elements. In addition, it was found that the employment of a low-permeability membrane at the lead element was important to maintain acceptable TDS in the permeate at either high TDS or high fouling potential of feed water.