The uneven microstructure and element distribution between the inner-layer zone (INZ) and the inter-layer zone (ITZ) resulting from the thermal cycling effect during the directed energy deposition process with the electric arc energy source (DED-Arc) can lead to inferior mechanical properties. In order to address this problem, the ultrasonic treatment of the 2319 Al-Cu alloy during the DED-Arc process is investigated to control the multi-regional microstructure quantitatively. Therefore, the effect of ultrasonic vibration during the DED-Arc process on grain morphology, distribution of precipitates and mechanical properties in different regions are explored in detail. The formation mechanism of differential microstructure is elucidated by using an ultrasonic-heat-flow coupling simulation model for the DED-Arc process. The results indicate that ultrasonic vibration refines the average grain size, leading to 16% and 40% reductions at the molten pool center (MPC) and boundary (MPB), respectively. However, the grains in the semi-melting zone (SMZ) experience coarsening due to the reduced temperature gradient after ultrasonic treatment. The enhanced melt flow rate is considered responsible for both the homogenization of Cu and the fragmentation of the θ-Al2Cu phase. The higher subgrain boundary density in the ITZ leads to an average microhardness of approximately 60 HV, which is lower than that found in the INZ (72.3 HV). Meanwhile, ultrasonic treatment increases the average strength and elongation by 38.1% and 17.5%, respectively, mainly through precipitation strengthening, which results in a strength increment of 91.6 MPa. The slip directions tend to be consistent after ultrasonic vibration, which is conducive to crystal sliding and displays excellent ductility.