A multi-scale model of the whole steel frame based on the substructure method was established. Matlab was used to simulate a 600 s synoptic wind for conducting the dynamic time-history analysis. The fatigue characteristic of the detailed structure was analyzed using the equivalent structural stress method. The critical point of wind-induced fatigue in the three-dimensional garage was explored. The rationality of using a multi-scale model based on the substructure method for analyzing the whole structure was assessed. The effects of flange docking mode， transition angle and cantilever beam length on the fatigue life of the structure were calculated. The results show that the wind-induced fatigue danger position of the three-dimensional garage is at the edge of butt weld between the lower flange of the beam and the cantilever segment on the weak axis side of the middle beam-column joint in the windward surface of the top second layer. The predictions from the multi-scale model structure based on substructure method are in good agreement with the second-order solid element model， satisfying engineering accuracy requirements. The stress concentration at the butt weld is effectively reduced by adopting a center-aligned flange welding mode. The fatigue life of the whole structure increases with the increase of the angle of the transition zone and the length of the cantilever beam segment.