The combination of gold nanoparticles (AuNPs) with chromium-substituted hydrotalcite (Cr-HT) supports makes very efficient heterogeneous catalysts (Au/Cr-HT) for aerobic alcohol oxidation under soluble-base-free conditions. The Au-support synergy increases with increasing Cr content of the support and decreasing AuNP size. In situ UV-Raman, X-ray absorption and photoelectron spectroscopic studies firmly establish that the strong Au–Cr synergy is related to a Cr3+ ¿ Cr6+ redox cycle at the Au/Cr-HT interface, where O2 activation takes place accompanied by electron transfer from Cr-HT to Au. The interfacial Cr6+ species can be reduced by surface Au–H hydride and negative-charged Au species to close the catalytic cycle. A study of kinetic isotope effect indicates that alcohol O–H cleavage is facilitated by the presence of Cr, making a-C–H bond cleavage step more rate-controlling. Accordingly, a dual synergistic effect of Au/Cr-HT catalysts on the activation of O2 and alcohol reactants is proposed.