Al-Cu-Mg aluminum alloys have been widely used in structural components due to their excellent mechanical properties, fatigue resistance, and processability. This review focuses on the optimization of fatigue performance in Al-Cu-Mg alloys and systematically summarizes the effects of key factors including elemental composition control, microstructural control, precipitate behavior, texture evolution, and dislocation regulation. Studies reveal that optimizing the Cu/Mg atomic ratio can tailor precipitate distributions and improve crack initiation resistance. Fine-grained microstructures enhance grain boundary strengthening and impede dislocation slip, thereby significantly retarding crack propagation. The combination of favorable texture types and high-angle grain boundaries can deflect crack paths and suppress straight-line crack growth. Moreover, the synergistic interaction between precipitates and dislocations is identified as a critical mechanism for enhancing fatigue life. Future developments should integrate high-throughput alloy design, nano-precipitate engineering, and intelligent monitoring technologies to promote the widespread engineering application of these alloys.