Sputter-deposited Al/CuO multilayers exhibit fast combustion reactions in which an exothermic chemical reaction wave -controlled by the migration of oxygen atoms from the oxide matrix towards the aluminum layers through interfacial layers- moves throughout the multilayer at subsonic rates (m/s to tens of m/s). We directly observed the structural and chemical evolution of Al/CuO/Al multilayers upon heating to 700 °C using high-magnification Transmission Electron Microscopy (TEM) and Scanning TEM (STEM), providing simultaneous sub-nanometrer imaging resolution and detailed chemical analysis. Interestingly, as deposited, the trilayer is characterized by two distinct interfacial layers: 4.1 ± 0.2 nm thick amorphous alumina and 15 ± 5 nm thick mixture of AlOx and CuxAlyOz, at the bottom interface and top interface respectively. Upon heating, we accurately characterized the evolving nature and structure of these interfaces which are rapidly replaced by the reaction terminal oxide (Al2O3). For the first time, we unraveled the release of gaseous O from the sparse columnar and defective CuO well below reaction onset (at ~200 °C) which accumulates at interfaces and contributes to initiate the Al oxidation process at the vicinity of native interfaces. The oxidation process is demonstrated to be accompanied by a continuous densification and modification of the CuO layer. Between 300 - 350 °C, we observed a brutal shrinkage of CuO layer (14% loss of its initial thickness) leading to the mechanical fracture in the top alumina growing layer. Consequently, this latter becomes highly permeable to oxygens leading to a brutal enhancement of the oxidation rate (× 4). We also characterized stressed-induced interfacial delamination at 500 °C pointing clearly mechanical fragility of the top interface after the CuO transformation. Altogether, these results permit to establish a multi-step reaction scenario in Al/CuO sputter-deposited films supporting to an unprecedented level a mechanistic assignation of Differential Scanning Calorimetry (DSC) peaks. This study offers potential benefits for the development of aging models enabling the virtual prediction of the calorimetric response of exothermic Al/CuO thin film reactions.