CO2 catalytic hydrogenation to CO will likely be an important part of CO2 mitigation and valorization processes. Recently, we have developed materials containing surface-formed Cu-Al spinel that act as active and stable catalysts for this reaction. Here, the fundamental characteristics of Cu-Al and Co-Al spinel catalysts were studied to understand the role of the spinel structure in its catalytic activity for the reverse water gas shift reaction. Based on the catalytic tests, Cu-Al spinel was found to have a higher catalytic activity. By means of catalysts characterization combined with theoretical studies, this increased activity was attributed to the higher number of oxygen vacancies on its surface which were formed because of the higher inversion degree of Cu-Al spinel, which in turn, resulted in the formation of a more disordered structure with cation substitution. We found that the oxygen vacancies were vital for CO2 adsorption and activation on the spinel surfaces.