Transition metal nanoparticles (NPs) are typically supported on oxides to ensure their stability, which may result in modification of the original NP catalyst reactivity. In a number of cases, this is related to the formation of NP/support interface sites that play a role in catalysis. The metal/support interface effect verified experimentally is commonly ascribed to stronger reactants adsorption or their facile activation on such sites compared to bare NPs, as indicated by DFT-derived potential energy surfaces (PESs). However, the relevance of specific reaction elementary steps to the overall reaction rate depends on the preferred reaction pathways at reaction conditions, which usually cannot be inferred based solely on PES. Hereby, we use a multiscale (DFT/microkinetic) modeling approach and experiments to investigate the reactivity of the Ni/Al2O3 interface toward water-gas shift (WGS) and dry reforming of methane (DRM), two key industrial reactions with common elementary steps and intermediates, but held at significantly different temperatures: 300 vs 650 °C, respectively. Our model shows that despite the more energetically favorable reaction pathways provided by the Ni/Al2O3 interface, such sites may or may not impact the overall reaction rate depending on reaction conditions: the metal/support interface provides the active site for WGS reaction, acting as a reservoir for oxygenated species, while all Ni surface atoms are active for DRM. This is in contrast to what PESs alone indicate. The different active site requirement for WGS and DRM is confirmed by the experimental evaluation of the activity of a series of Al2O3-supported Ni NP catalysts with different NP sizes (2-16 nm) toward both reactions.