Numerous studies have been devoted to uncovering how the properties of nanoparticles (NPs), such as size, shape, chemical state and interaction with the support, affect their catalytic activity. To investigate the correlation among structure, oxidation state, and electrocatalytic activity, Au NPs with narrow size distributions (1 to 10 nm) were prepared via inverse micelle encapsulation by utilizing polystyrene-b-2-vinylpyridine block copolymers. The encapsulated nanoclusters were deposited onto conducting substrates and oxygen plasma etching was used to remove the residual polymeric ligands. X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), scanning electron microscopy (SEM), and X-ray absorption spectroscopy (XANES/EXAFS) were employed to characterize dynamic changes in the structure and chemical state of the NPs ex situ and under operando conditions. Results from these studies for the 2-propanol electrochemical oxidation under alkaline media over Au nanoparticles showed that a size-dependent trend was observed, with increasing activity (increased current density and lower overpotential) with decreasing NP size. Moreover, an enhanced endurance against poisoning by the acetone intermediate was also obtained for small NP catalysts. The insight into the dynamic evolution of the chemical state and NP structure was verified by operando X-ray absorption fine-structure (XAFS) measurements. It also cast light on the phenomenon of catalyst deactivation and the nature of the catalytically active sites.