Operando DRIFTS is used to identify the nature and the role of the surface sites of hydroxyapatites (HAps) involved in the catalytic transformation of ethanol to n‐butanol. The surface processes occurring upon a first reaction step followed by a step under He flow greatly influence the reactivity of HAps in a subsequent second reaction step. Ethanol is found to be mostly activated by the basic OH− groups of HAps, as indicated by the concomitant recovery of ethanol conversion and OH− groups under He flow. The drastic changes in selectivity observed during the second reaction step reveal the key role of acidic sites cooperatively acting with basic sites for basic reaction steps. Once the POH groups are poisoned by extensive formation of polymeric carbon species and the Ca2+ sites are available, the production of acetaldehyde is drastically promoted at the expense of that of n‐butanol. It is concluded that i) acetaldehyde acts as an intermediate in the formation of n‐butanol, and ii) various active sites are involved in the key basic reaction steps such as Ca2+−OH− and POH−OH− acid‐base pairs in the dehydrogenation of ethanol to acetaldehyde and the aldol condensation for n‐butanol formation, respectively.