The presence of active metal nanoparticles on the surface significantly increases the electrochemical performance of ABO3 perovskite oxide materials. While conventional deposition methods can improve the activity, in situ exsolution produces nanoparticles with far greater stability. The migration of transition metal atoms toward the surface is expected to affect the exsolution process. To study the energetics, we use ab initio computations combined with experiments in a SrTiO3-based model system. Our calculations show that Ni preferentially segregates toward the (100)-oriented and SrTiO-terminated surfaces, note that this orientation is identical to one reported by the Irvine and Gorte groups. Vacancies in the Sr-site and O-site promote the segregation of Ni, while placing La on the Sr-site has an opposite effect. The corresponding experiments are in agreement with the computational predictions. Fast nanoparticle growth and activity enhancement are found in STO system with Sr vacancies and without La. The approach developed in this Letter could be used to study the mechanism of exsolution in other material systems, and possibly lead to the development of new compositions capable of nanoparticle exsolution with higher activity and stability.