Limited stability of metal nanoparticles hinders their long-term uses and applications. For metal nanoclusters, this is even more critical, as physicochemical properties rely on the structure of only a few hundred atoms. Here, we study the irreversible change that Au₂₅(SR)₁₈ suffers upon interaction with 2D metal surfaces. Experimental and density functional theory results allow us to identify the triggering factors of the decomposition process. Our thermodynamic-based approach can be extended to other metal nanocluster/substrates, turning it into a useful tool for predicting the nanoscale stability of these systems.Facultad de Ciencias ExactasInstituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas