The structure of a catalyst has a strong impact on its performance. Here we investigate the physicochemical properties of Ni/CeO₂ in an attempt to draw structure–activity relationships for CO₂ methanation. A combination of characterisation methods (X-ray diffraction (XRD), 4D Scanning Transmission Electron Microscopy (4D-STEM), CO chemisorption and oxygen storage capacity study etc.) clearly demonstrates the effect of Ni crystallite size, Ni availability (i.e. catalytically accessible Ni) and oxygen vacancies at the Ni-CeO₂ interface in Ni/CeO₂ during CO₂ methanation. Among them, the role of exposed Ni active sites is highlighted, and two possible optimisation schemes i.e. changing the support calcination temperature and the final calcination atmosphere are proposed to obtain a better dispersal of Ni NPs (nanoparticles) on CeO₂. Both modification methods do not affect the reaction route, and the activity differences of Ni/CeO₂ can be explained by the various hydrogenation rate of formate species, as confirmed by in situ diffuse-reflectance infrared Fourier-transform spectroscopy (DRIFTS) measurements.