In this study, we investigated the Ni/CeO2/Al2O3 catalyst system to explore the influence of different synthesis parameters on interfacial phenomena and their impact on CO2 methanation. The focus was on the textural properties of alumina, ceria loading, and the synthesis method of supported Ni, in relation to the catalyst’s activity and CH4 selectivity. Among the catalysts studied, Ni-20Ce/mpAl demonstrated promising results, with an XCO2 value of 70% and SCH4 value exceeding 94% at 350 °C. We observed that medium- and high-porosity alumina facilitated better ceria dispersion, while Ni-CeO2 cogrowth led to small Ni crystallites (∼4 nm) that increased in size after 8 h of reaction. This catalyst exhibited several advantageous features for CO2 methanation, including a high concentration of oxygen vacancies (confirmed through Raman studies) and a significant presence of surface Ce3+ species (validated by XPS and EPR studies). It also displayed excellent carbonyl activation capacity, high H-spillover capability, and strong SMSI phenomena. CO2-TPD and charge transfer Bader analysis confirmed the basic (Lewis) character of the catalyst’s surface. Specifically, Ce3+ species, along with Ni atoms, provided suitable dual sites for CO2 adsorption at the Ni-ceria interface, forming Ni···O-C-O···Ce3+ entities. Furthermore, our analysis using operando SSITKA-DRIFTS revealed the active participation of both Ni and the support in the CO2 methanation reaction, validating the ab initio studies. Notably, linear and bridged adsorbed CO species (COL and COB) on the Ni surface, as well as bicarbonates (HCOOOs), were identified as active reaction intermediates involving Ce3+-OH and Al3+-OH entities. Comparing the thermal stability of carbonate-type intermediates to that of carbonyls, a CO-mediated mechanism emerged as the predominant pathway over the Ni-20Ce/mpAl catalyst.