In this paper, the microstructure characteristics, fatigue properties and fracture mechanism of 95 mm Al-Cu-Li alloy hot-rolled thick plates 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 hot-rolled thick plate were both anisotropic. The mechanical properties of the L direction are better than those of the ST direction, but the fatigue properties are worse than those of the ST-direction. The fatigue crack sources of Al-Cu-Li alloy thick plates mainly appear on the surface of the sample, near the surface of the inclusions and grain boundaries. During the crack propagation process, the crack propagation path in the LT direction was more tortuous than that 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 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 that in the L direction.