This paper aims at investigating the influence of the direction of wind and seismic ground motion on the structural response of four-legged jacket support substructures for bottom-fixed Offshore Wind Turbines located in areas with non-negligible seismic risk. To do that, a parametric analysis that considers thirteen seismic shaking directions, seven wind directions and four earthquake records is carried out. The results are presented in terms of accelerations, axial forces, bending moments and shear forces in the jacket substructure. The NREL 5 MW wind turbine supported on the jacket designed for the phase I of the OC4 project is considered. The response of the system is simulated using an OpenFAST model that takes into account multi-support seismic input, soil–structure interaction and kinematic interaction. The results show that load combinations with aligned wind and ground motion directions are never the worst-case scenario. On the contrary, the largest accelerations are found when the shaking direction acts along the side-to-side direction, and the most significant internal forces are usually found when the ground motion is aligned with one of the diagonals of the base of the jacket and not aligned with the wind direction. The paper also discusses the specific ranges of the angle of misalignment between wind and seismic shaking directions within which the maximum internal forces are expected to be found.