Abstract: To study the thermal stability of the nanocrystalline alloy system, a multiscale coupling model was developed by combining the first principles with thermodynamic calculation. Thus, the thermodynamic properties of nanocrystalline alloys can be evaluated considering doping elements, solute concentration, grain size and temperature. The critical conditions of destabilization and parameters for tailoring stability of the nanograin structure can be predicted. For the alloy system, the critical grain size for the thermal stability and its influencing mechanisms were proposed for the nanocrystalline systems. For the solid solution systems with solute-segregating, the mechanisms for controlling the thermal stability by matching the solute concentration and initial grain size were disclosed. The model calculations were confirmed quantitatively by the experimental results, and nanocrystalline alloys with high thermal stability were prepared.