The effects of minor additions of the transition elements Zr, Ti, and V on the microstructure, mechanical properties, and out-of-phase thermomechanical fatigue behavior of 224 Al-Cu alloys were investigated. The results revealed that the introduction of the transition elements led to a refined grain size and a finer and much denser distribution of θ″/θ′ precipitates compared to that of the base alloy, which enhanced the tensile strength but reduced the elongation at both room temperature and 300 °C. Constitutive analyses based on theoretical strength calculations indicated that precipitation strengthening was the primary mechanism contributing to the strength of both tested alloys at room temperature and 300 °C. The out-of-phase thermomechanical fatigue test results showed that the addition of transition elements caused a slight decrease in the fatigue lifetime, which was mainly attributed to the reduced ductility and higher peak tensile stress at low temperatures. During the fatigue process, the transition element-added alloy exhibited a lower coarsening ratio, indicating higher thermal stability, which mitigated the negative impact of the reduced ductility on the fatigue performance to some extent. Considering their various properties, the addition of Zr, Ti, and V is recommended to improve the overall performance of Al-Cu 224 cast alloys.