The internal mechanisms of nucleation and growth of L12-Al3RE (RE = Sc, Y, La–Lu) second phases in Al alloys were investigated by combining first-principles calculations with quasi-harmonic approximation (QHA). The calculated results show that the diffusion rate Ds and chemical potential ΔGV increase with the increase of temperature. With the increase of atomic number, the Ds and the strain energy ΔECS increase firstly from Sc to La, and then decreases, while the calculated interface energy γα/β and ΔGV show opposite tendency. Based on above calculated results, the critical nucleation radius R∗ and coarsening rate KLSW are obtained from the classical nucleation theory (CNT) and LSW model of the Ostwald ripening of particles, respectively. With the increase of atomic number, the R∗ increases firstly, and then decreases for all planes at finite temperatures. Whereas the KLSW shows opposite variation to the R∗. From this point of view, it is reasonably speculated that Y and later RE elements can replace the expensive Sc for heat-resistance Al alloys. The solubility c∞ of particles is usually very small at low temperature, and there is obvious solubility only when the temperature reaches 600 K. The surface energies Esur of Al3RE compounds and Al solid solution are respectively larger and smaller than that of pure Al, respectively, except for the surface (001) and (110) of Al3La. For all planes, with the increase of atomic number of RE, Esur decreases firstly from Sc to La, and then increases linearly to Lu. These results are helpful for designing high performance heat-resistance Al alloys.