Fine and dispersed Mg–Ti–oxide inclusions, which act as heterogeneous nucleation sites for intragranular ferrite, have been acknowledged as an effective method for grain refinement. In this paper, the nucleation and growth mechanisms of ferrite on Mg–Ti-oxides surface were investigated through first-principles calculations and solid-state pressure bonding experiments. The calculated results show that the formation of cation vacancies is the limiting step for Mn solute atom absorption by Mg–Ti-oxides. As determined by the lower covalency and ionicity of the Mg–O bond compared to the Ti–O bond in Mg–Ti-oxides, Mn atoms will be efficiently absorbed by occupying the Mg vacancies. The experimental results demonstrate that MgTiO3 with the maximum Mn-depleted zone (MDZ) width is the most effective for ferrite nucleation, which is consistent with the calculation results. As a representative, the Fe(110)/MgTiO3(001) interface with the lowest planar disregistry (3.16%) was selected to analyze growth behaviors. Due to charge accumulation and variation, Fe atoms are more likely to gather on the Mg–O terminal MgTiO3(001) surface and form (Mg–O)–Fe-1 interfaces. Its adhesion work and interface energy are 1.74 and 2.46 J/m2, respectively. The present study illustrates the nucleation and growth mechanisms of ferrite on Mg–Ti-oxides, providing theoretical support for the application of Mg–Ti-oxide inclusions in oxide metallurgy.