As the dimension of the floating substructures for ultra-large wind turbines increases, the flexibility of the large-volume floating substructures may increase to the extent that may significantly affect the dynamic responses of an ultra-large semi-submersible floating offshore wind turbine (FOWT), which introduces new challenges in capturing relevant physical effect in numerical simulation analysis. This paper describes a newly designed semi-submersible substructure for the Technical University of Denmark (DTU) 10 MW wind turbine, and the substructural flexibility is considered in aero-hydro-servo-elastic dynamic simulations by extending the simulation OpenFAST Code, including wave-structure interactions. A comprehensive comparison of flexible and rigid large-volume substructures models is presented to highlight the effect of substructural flexibility on the hydrodynamic loads and dynamic responses of the integrated FOWT system by implementing a fully coupled simulation analysis in the time domain. Additionally, the difference of flexible and rigid large-volume substructures models on the structural fatigue behavior of the novel semi-submersible FOWT is investigated and discussed by computing ultimate and damage-equivalent loads (DELs) for selected environmental conditions. The results show that the substructural flexibility has a significant impact on fatigue damage of the integrated FOWT system in operating sea states than that in extreme sea state.