The nucleation properties and stability of the ordered precipitates in Al-Sc-Er alloy were extensively studied by first-principles calculation. The calculated substitutional formation energy reveals that the dissolved Sc or Er in the Al matrix is very favorable to substitute the X sublattice site in L12-Al3X (X=Sc/Er). The calculated solubility curve demonstrates the significant contribution of vibrational entropy to nucleation. The interface energies for Al/Al3Sc, Al/Al3Er and Al3Sc/Al3Er were calculated in the three directions of [100], [110] and [111], and we find that the interface structure in (100) plane is the most desirable, and the interface energy of Al/Al3Er is the largest. Regardless of temperature and Sc/Er ratio, the L12-Al3ScxEr1-x precipitation phase mainly forms as the core-shell structure with Al3Er as the core and Al3Sc as the shell due to lower nucleation energy. The core-shell structure behaves higher stability once the particle radius is greater than 1 nm. Furthermore, the thermodynamic driving force for the segre-gating of Si or Zr in Al-Sc-Er alloy should accelerate the precipitation kinetics, where Si partitions occur preferentially to the Al3Er and Zr partitions preferentially to the Al matrix. Overall, these theoretical results can offer solid explanations to the available experimental results.