In this paper, the compression behavior of Al-Cu-Mg-Ag bi-crystal samples at room temperature under different orientation combinations was studied. The stress-strain distribution of bi-crystal samples during the compression process was studied based on the crystal plastic finite element method (CPFEM). The deformation mismatch and slip transfer caused by the orientation combination of bi-crystal are discussed. The results show that the Al-Cu-Mg-Ag alloy bi-crystal samples with different orientations exhibit an anisotropic hardening response under compression. The combination of soft and hard orientation can coordinate the dislocation drive of the yield point, delay the elastoplastic transition of the yield point, and greatly improve the strength of the alloy. The mechanism of high strength of heterogeneous structure is proposed in this paper, which provides an important reference for the design of high strength heat resistant aluminum alloy for automobiles.