This study presents a CFD (computational fluid dynamics)-assistant multi-scale modeling and optimization strategy for synthesizing cooling water systems which incorporates multiple closed wet cooling towers (CWCTs) installed with plain tubes. The utilization of CFD is capable of providing accurate and visual results with respect to complex thermal and fluid flow phenomena that can be used to explore the synergistic mechanism of multi-parameter for CWCTs. Based on CFD results, a systematic reduced order model (ROM) for CWCTs is developed by closely approximating the high-fidelity CWCTs models through integrating principal component analysis (PCA) with Kriging-based surrogate model. This ROM is accessible to the desired result through input data without accounting for the complex geometries and detailed thermal-hydraulics property models. The proposed CFD-assistant ROM for the CWCTs is applied to enhance solution convergence and obtain optimal results of cooling water systems. An industrial case study is used to demonstrate the superiority of the proposed CFD-assistant strategy for the cooling water system synthesis and optimization.