A cross wave simulation method by computational fluid dynamics (CFD) method and volumn of fluid (VOF) wave-making technique was established to study the difference of ship motion responses in multi-directional and uni-directional waves. The momentum source method and wave forcing were used to superimpose waves to simulate cross wave. The motion behavior of a S175 ship in cross waves with different wave parameters was studied using overset mesh technique and dynamic fluid body interaction (DFBI) module. The ship motion responses in bi- and uni-directional waves were comparatively analyzed and the motion characteristics of ships on different navigational routes in a cross wave field were analyzed. Results indicate that the motion responses and green water on deck in bi-directional waves are generally much greater than those in uni-directional waves. And, the ship has obvious roll motion in cross waves. However, ship motions and green water on deck can be largely reduced by adopting the reasonably optimized navigational route and strategy, which would improve the navigation safety of the ship in cross waves and provide suggestions for the sailing safety when the ship encounters cross waves.