Practical modeling for assessing the efficiency of a full-scale reverse osmosis (RO) system may be a challenging task. This is because the operating conditions of RO systems can change significantly in actual practice owing to high seasonal variations and different progress of membrane fouling during long-term filtration. Accordingly, it is difficult to reliably model the RO performance if such conditions are excluded. In this study, we model a fullscale installation of a RO membrane system, considering actual operations of the industrial water treatment plant. A numerical model is built to describe spatiotemporal behavior of (water, salt, and foulant) mass transport inside a full-dimension pressure vessel. By performing a global sensitivity analysis, we evaluate the relative importance of key influential factors on model accuracy and specific energy consumption (SEC). The model and its parameters are optimized based on the sensitivity result and validated using best-fitted time-series measurement data of 3875 h. The results demonstrate the practical behaviors of fouling development and separation performance of the primary RO process. A regression tree analysis of SEC for 27 different operational scenarios in simulations may benefit decision making for energy efficient RO. Results reveal the high dependence of SEC on cleaning frequency in the feed temperature range.