In this paper, the microstructure characteristics, fatigue properties and fracture mechanism of 95mm Al-Cu-Li alloy thick plate in different orientations were studied by fatigue testing machine, scanning electron microscope (SEM) and transmission electron microscope (TEM). The results showed that the mechanical properties and fatigue properties of Al-Cu-Li alloy thick plate were both anisotropic. The law of mechanical properties was LT direction (width direction) > L direction (length direction) > ST direction (height direction) and the law of fatigue properties was LT direction>ST direction>L direction. Fatigue crack sources of Al-Cu-Li alloy thick plate mainly appeared on the sample surface, near-surface inclusions and grain boundaries. During the crack propagation process, the crack propagation path in the LT direction was more tortuous than in the L direction, and the ST direction had a typical cleavage characteristic. The morphology of the instantaneous fracture zone was similar to that of the tensile fracture. The L-direction and LT-direction were mainly plastic fracture, and the ST-direction was mainly brittle fracture. The more grain boundaries, the greater the crack propagation resistance, and the undissolved second phase in the LT direction and ST direction can effectively hinder the crack propagation, resulting in better fatigue performance than the L direction.