CuAl2O4 based mixed oxides were used as heterogeneous catalysts for ozone activation to degrade organics in aqueous solution. The solids were thoroughly characterized by SEM/EDS, N2 physisorption, XRD, FTIR, Pyridine-FTIR, TEM and XPS. We demonstrated that the solid precursor calcined at 300 °C exhibited the best catalytic ozonation activity with respect to CuAl2O4 spinel phase obtained at higher temperatures. Such performance was attributed to the better textural properties and a higher density of active sites (hydroxyl groups and Lewis acidity). Specifically, the mixed oxide/O3 process allows to reach a near complete color removal of the dye solution (100 mg L−1) in 25 min at neutral pH. Corresponding reaction rate value was measured at 0.112 min−1 and was clearly higher compared with the single oxide ozonation process (0.071 min−1 for CuO/O3 and 0.074 min−1 for Al2O3/O3). Then, we proposed that such catalytic performance was related to a synergistic function between ≡Cu2+ and ≡Al3+, which took part of a mechanism of radical formation. In such mechanism, present ≡Al3+ could act as a reservoir for surface active sites such as hydroxyl groups and Lewis acid sites, while ≡Cu2+ could provide the possibility of electron transfer with ozone for the enhancement of radical generation. We suggested that the interaction between chemisorbed ozone and surface hydroxyl groups initially stabilized on ≡Al3+ initiated the generation of reactive radical species. This interaction led as well to the formation of surface adsorbed HOradical dot and few O2radical dot− on ≡Cu2+ Lewis acid sites. Besides, the interfacial redox reaction with ozone is favored by the presence of ≡Cu2+ following the sequence of ≡Cu2+/≡Cu+/≡Cu2+ redox cycle.