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In this paper, a method for the assembly of multi-domain substructures with general joints is proposed. Modal domain and physical domain substructures can be coupled in a unified framework. Specially, the physical domain substructures are represented using the impulse response functions of substructures. The modal domain substructures are generated using the Craig–Bampton method. With the introduction of general joints, complex connections like hybrid rigid-elastic or nonlinear connections are able to be considered. Meanwhile, only degree of freedoms directly associated with the joints are retained for the synthesis that makes this method quite suitable for local nonlinear structures. The validity of the proposed method is demonstrated by numerical examples. And the application to the dynamics of a practical lunar lander is provided. The results show that the proposed method possesses high precision and is quite efficient with the reduced substructures employed and a few joints degree of freedoms involved.