In the present paper, the high cycle fatigue (HCF) of a novel 211Z.X aluminum alloy with high strength was studied under hot-rolling and as-cast states at room temperature. The effects of microstructure and distribution of precipitated phases and impurities on the mechanical properties, HCF performances, fatigue microcrack initiation, and propagation behavior of the 211Z.X alloy were studied by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and energy dispersive spectrometry (EDS). The HCF S–N curves, P–S–N curves and Goodman fatigue diagrams of 211Z.X alloy consisting of two microstructures were drawn. The results suggested that the fine and dispersive distribution of the second phases improved the strength of the alloy. The formation of short-bar and spherical precipitates promoted coordinated deformation of the alloy. This promoted higher microcrack initiation resistance of 211Z.X alloy with a hot rolling state than in the cast state. As a result, the HCF properties of the hot-rolling alloy were better than those of the cast alloy. In sum, these results look promising for future reliable design of engineering structures and application of new aluminum alloys.