The microstructural evolution and properties of an Al-Cu-Li alloy with Mg and Zn microalloying (Al-3.5Cu-1.5Li-0.5Mg-0.4Zn-0.3Mn-0.12Zr-0.06Ti) ingot subjected to homogenization (second-step annealing at 500 °C for 24 h following first-step annealing at 400 °C for 8 h) were investigated. Mg-Zn atom clusters were enriched at the end of dendrites as well as low-melting eutectic phases such as S (Al2CuMg), T2 (Al6CuLi3), TB (Al7.5Cu4Li) and T1 (Al2CuLi) in the as-cast alloy. During homogenization, Mg-Zn atom clusters diffused from the segregation to the vacancies, leading to the dissolution of the low-melting eutectic phases. Not only Al3Zr particles were observed at 500 °C, but more fine and uniform spherical dispersoids appeared, which were assumed as Al3(ZrxTiyLi1−x−y). Mg and Zn microalloying can promoted the nucleation of Al3Zr and Al3(ZrxTiyLi1−x−y) dispersoids, as well as T (Al20Cu2Mn3) phases, which all inhibited recrystallization effectively and improve the uniformity of the grains due to the strong pinning effect. The yield ratio was decreased from 0.81 to 0.52 with the yield strength decreased from 172 MPa to 61 MPa, which showed better plastic deformation ability of the alloy subjected to homogenization. In addition, the dissolution of low-melting eutectic phases and formation of Al3(ZrxTiyLi1−x−y) dispersoids resulted in the significant improvement on thermal stability.