The presented research deals with the simulation of ship’s maneuvering performance in adverse weather conditions. A 4-DoF (surge, sway, yaw and roll) nonlinear maneuvering model is formulated and solved in the time domain by use of MATLAB’s software environment, in which several subsystems referring to the calculation of the hull, propeller and rudder forces/moments are integrated. The maneuvering derivatives and acting forces/moments are being alternatively estimated by use model experimental data, of semi-empirical relationships and the application of potential theory 3D panel codes and CFD-RANS solvers. The wave-induced forces/moments are herein considered through the mean second order wave forces/moments, which are pre-calculated and disposed to the maneuvering simulation solver as response surfaces. The validation of the developed theoretical/numerical approaches is herein demonstrated by in depth studies on the maneuvering coefficients and on typical maneuvers of the DTC standard containership in waves and the KVLCC standard tanker. Associated model experiments were conducted by MARINTEK for the DTC containership and CEHIPAR for the KVLCC tanker in the frame of the EU funded project SHOPERA.