Due to the outstanding advantages such as low density, high modulus, and high damage tolerance, cast Al-Li alloys are highly promising metallic materials for load-bearing applications in the coming decades. However, compared to their wrought counterparts, the mechanical properties of these alloys, particularly the ductility, are still unsatisfactory, which severely limits their further applications. Here, we report that the mechanical properties of cast Al-Li alloys can be significantly improved by regulating various nano-phases during aging. Results show that the introduction of 0.2 wt% Zr in the Al-2Li-2Cu-0.5 Mg alloy contributes to grain refinement by providing a large number of primary Al3Zr particles acting as ideal heterogeneous nucleation sites for the α-Al matrix. During subsequent aging, Al3Li tends to nucleate and grow on the Al3Zr surface to reduce the interfacial energy and form a nano-complex with a core–shell structure in 0.2Zr alloy. Then, the Al3Li shell can serve as an effective nucleation site for the T1 and θʹ phases. Density functional theory (DFT) calculations indicate that nucleation of T1 and θʹ on the Al3Li shell reduces the interfacial energy, which promotes their uniform precipitation. In this case, unique Al3(Zr, Li) particles and higher density of finer T1 and θʹ phases provide a substantial Orowan strengthening effect, alleviating the stress concentration. In addition, grain refinement improves the coordination of plastic deformation in 0.2Zr alloys. As a result, the ductility of 0.2Zr alloy increases from 3.6 % to 7.1 % compared to the Base alloy, accompanied by a 66 MPa increase in ultimate tensile strength. This work is expected to offer a new engineering approach to designing high-performance cast Al-Li alloy components with broad application prospects.