The fatigue performance of high-strength Al-Cu-Mg alloys is generally influenced by the process of creep age formation when applied to acquire higher strength. The results show that creep aging accelerates the precipitation process, leading to a more uniform precipitation of strengthening phases in grains, as well as narrowed precipitation-free zones (PFZ). Compared with the artificially aged alloy, the yield strength and hardness of the creep aged alloy increased, but the fatigue resistance decreased. In the low stress intensity factor region (ΔK ≤ 7 MPa·m^1/2), the fatigue crack propagation (FCP) rate was mainly affected by the characteristics of precipitates, and the fatigue resistance noticeably decreased with the increased creep time. In a 4 h creep aged alloy, the microstructure was dominated by Cu-Mg clusters and Guinier-Preston (GP) zones, while S″ phases began to precipitate in the matrix, showing better fatigue resistance. After aging for 24 h, the needle-shaped S’ phases were largely precipitated and coarsened, which changed the mode of dislocation slip, reduced the reversibility of slip, and accelerated the accumulation of fatigue damage. In stable and rapid crack propagation regions, the influence of precipitates on the FCP rate was negligible.