Electron beam freeform fabrication (EBF3) additive manufacturing technique has been successfully employed to print the non-weldable Al-5Cu thin-walled parts through an optimized set of process parameters. Post-heat treatment is conducted to engineer the desirable microstructure containing multiple nanostructures, i.e., the nanoscale θ" and θ' precipitates, stacking faulted zones and Al-Cu-Cd clusters, leading to a high-strength Al-5Cu alloy with good ductility. The grain formation mechanisms are revealed via a combinatorial simulation and experimentation. It is shown that EBF3 process can produce three different types of grain microstructures: fully equiaxed, fully columnar, and the mixture. In the layerwise melt pool solidification process, wide partially melted zone is observed to favor the formation of equiaxed grains due to its inheritance characteristic. After solution and aging heat treatment, Al-Cu-Cd nanoclusters (∼ 2 nm in Dia.) are generated, which facilitates the formation of nanoscale stacking faulted zones (∼11 nm). Meanwhile, as heterogeneous nucleation sites, Al-Cu-Cd nanoclusters effectively promote θ'-Al2Cu phase (∼ 19 - 114 nm) precipitation to enable the coexistence with fine θ"-Al3Cu precipitates (∼ 7 - 37 nm). The multiscale microstructure, especially incorporating the newly identified nanoscale stacking faulted zones, activates multiple strengthening mechanisms. Consequently, its tensile properties at room temperature reach an ultimate tensile stress of ∼ 496.5 MPa, yield strength of ∼ 435.7 MPa, and elongation of ∼ 9.6%, which are superior to other as-cast and additively manufactured Al-Cu alloys. This work offers a promising processing route to directly fabricate high-strength near-net-shape Al-Cu alloy parts for the aerospace and automotive industries.