In this paper, a methodology for designing mooring system deployment for vessels at varying water depths isproposed. The Non-dominated Sorting Genetic Algorithm-II (NSGA-II) is combined with a self-dependently developed vessel-mooring coupled program to find the optimal mooring system deployment considering both station-keeping requirements and the safety of the mooring system. Two case studies are presented to demonstrate the methodology by designing the mooring system deployments for a very large floating structure (VLFS) module and a semi-submersible platform respectively at three different water depths. It can be concluded from the obtained results that the mooring system can achieve a better station-keeping ability with relatively shorter mooring line when deployed in the shallow water. The safety factor of mooring line is mainly dominated by the maximum instantaneous tension increment in the shallow water, while the pre-tension has a decisive influence on the safety factor of the mooring line in the deep water.