Understanding the microstructural evolution and anisotropic behavior of Al-Li alloys after pre-deformation in different directions is crucial for optimizing their forming performance. This study investigates the microstructural evolution in AA2099 Al-Li alloy rolled sheets after pre-deformation in the extrusion direction (ED) and transverse direction (TD), and the resulting changes in mechanical properties during subsequent tensile deformation. A crystal plasticity finite element model (CPFEM) was established to quantitatively analyze the link between pre-deformation direction and the microstructural response during the hardening stages of tensile deformation. The results showed that the differences in mechanical properties due to pre-deformation direction are mainly attributed to the variations in volume fraction and diameter of the T1 precipitates. The contributions of T1 phase to yield strength are estimated to be 239 MPa (ED) and 223 MPa (TD), respectively. An increase in T1 (Al2CuLi) phase volume fraction and a decrease in phase diameter lead to higher average von Mises stress and average maximum principal strain values during the hardening stages.