There is a renewed interest in designing solid acid catalysts particularly due to the significance of Lewis acid catalyzed processes such as Friedel–Crafts acylation and alkylation and cellulose hydrolysis for the development of sustainable chemistry. This paper reports a new focus point on the properties of supported CuO on silica, a material that up to now has been considered only as the precursor of an effective hydrogenation catalyst. Thus, it deals with a re-interpretation of some of our results with supported copper oxide aimed to unveil the root of acidic activity exhibited by this material, e.g. in alcoholysis reactions. Several techniques were used to highlight the very high dispersion of the oxide phase on the support allowing us to ascribe the acidic behavior to coordinative unsaturation of the very small CuO particles. In turn this unsaturation makes the CuO particles prone to coordinate surrounding molecules present in the reaction mixture and to exchange them according to their nucleophilicity.