Under an industry-related high-temperature oxidation atmosphere, the structure and chemical states of metal nanocatalysts meeting sustainable development challenges change dramatically, deteriorating the activity and/or lowering the yield. Theoretically revealing the mechanisms of oxygen-induced structure evolution and establishing a framework to distinguish them are vital to improving the operando stability and rational design of metal nanocatalysts. Here, we studied the oxygen-induced disintegration and Ostwald ripening of Ni, Cu, Pt, Pd, and Ag nanoparticles on TiO2(110) using first-principles-based thermodynamic and kinetic simulations. It was found that oxygen promotes Ostwald ripening via the formation of Ag/Ag–O and Pd intermediates on the support and volatile gaseous PtO2 complexes, induces disintegration of Ni nanoparticles to Ni–O complexes, and leads to the formation of copper oxide. These differences in the deactivation pathways can be attributed to the dependence of the ripening activation energies and disintegration free energies on the interaction between metal atoms/complexes and TiO2(110). Revealed knowledge and corresponding models provide valuable insights into the general mechanisms governing the structural evolution of supported nanocatalysts under reaction conditions.